Tricyclic benzazepine and benzothiazepine derivatives

ABSTRACT

The tricyclic benzazepine and benzothiazepine derivatives represented by the formula (I) and pharmacologically acceptable salts thereof are disclosed. ##STR1## wherein Z represents CO, --CR 6  R 7  -- or --S(O) n , R represents hydrogen, alkyl, phenylalkyl, or a protective group of a triazole ring, R 1  -R 5  represent hydrogen, alkyl, alkenyl, alkoxy, amino, oxim or hydroxyl. These compounds have anti-allergic effect and are useful for the treatment and prophylaxis of allergic diseases.

This application is a 371 of PCT/JP 94/02282, filed 28 Dec. 1994 whichclaims the priority of Japanese Applications 5/337189 filed 28 Dec. 1993and 6/202349 filed 26 Aug. 1994.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to novel tricyclic benzazepine compounds,novel benzothiazepine compounds having anti-allergic activities,synthetic intermediates thereof, and processes for preparing them.

2. Background Art

It has been recently shown that allergic reactions such as immuneresponses caused by a variety of irritations include immediate typeresponses occurring just after irritation and delayed type responsesoccurring after several hours of irritation (see, for example "LateAsthmatic Responses", P. M. O'byrne, J. Dolovich and F. E. Hargreave,Am. Rev. Resppir. Dis., 1987, 136:740-751). The delayed responses, inparticular, have been regarded as important to control.

In clinical aspects, there are few agents which have sufficient efficacyagainst the delayed allergy. It is thus desired to develop an agentwhich exhibits excellent therapeutic effects on either response ofimmediate type and delayed type.

There has hitherto been known sodium cromoglycate as a typical agent forsuppressing allergic responses of immediate type and delayed type.However, this exhibits no effectiveness on oral administration and thusis clinically administered by inhalation.

However, it is sometimes difficult to administer properly to infants orlittle children by inhalation or to administer continuously to patientssensitive to inhalating irritation.

Because of these backgrounds, it has been desired to develop a compoundwhich inhibits both immediate and delayed allergic responses, can beadministered orally and has an excellent efficacy.

Furthermore, in recent years, a number of studies have been done onanti-allergic agents and anti-asthmatic therapeutics, among whichtri-cyclic compounds containing a seven-membered ring have beenreported. For instance, dibenzoxepin derivatives are disclosed inJapanese Patent Laid-Open Publication Nos. 10784/1988 and 78292/1993,and Chemical & Pharmaceutical Bulletin, 39 (10), 2724-2728 and 2729-2733(1991), dibenzoxazepin derivatives in Japanese Patent Laid-OpenPublication Nos. 184963/1991, 211071/1992 and 65257/1993, and EuropeanPatent EP 5180720, and dibenzocycloheptene derivatives in InternationalPatent WO/93-13068.

Also, heterocyclic ring-containing compounds have been reported asanti-allergic agent. For instance, dibenzoxepinopyridine derivatives aredisclosed in European Patent EP 515158, benzocycloheptathiophenederivatives in Japanese Patent Laid-Open Publication Nos. 294277/1991,and 226916/1992, benzocycloheptapyridine derivatives in Japanese PatentLaid-Open Publication No. 59040/1993, triazoloheptapyridine derivativesin Japanese Patent Laid-Open Publication No. 59040/1993,triazolobenzoxepine derivatives in Journal of Chemical Research (S),400-401 (1984), thieno(pyrazolo-, thiazolo-)benzothiazepine derivativesin European Patent No. 547705.

Some of these derivatives have been reported to have side-effects oncentral or cardiovascular systems and thus to have a problem that theanti-allergic action be separated from the central actions includingcalmative, antidepressant or anxiolytic actions or the cardiovascularactions including hypotensive or anti-thrombotic actions. Among thosecompounds having similar structures, cyproheptadine hydrochloride isonly available as an anti-allergic agent.

As for the additional similar compounds, there have been describedpyridobenzoxazepine derivatives as HIV-1 reverse transcriptaseinhibitors in Japanese Patent Laid-Open Publication No. 178390/1992,triazolobenzoxazepine derivatives as anti-depressant in Journal ofHeterocyclic Chemistry, 22, 1693-1701 (1985), and triazolobenzodiazepinederivatives as anti-psychotic agents in Journal of Medicinal Chemistry,32 (10), 2375-2381 (1989).

However, there has been described, as far as the present inventors know,no tricyclic benzazepine compound containing a triazole ring.

SUMMARY OF THE INVENTION

The present inventors have now found that some of the tricyclicbenzazepine and benzothiazepine compounds have an excellentanti-allergic effect.

Furthermore, the present inventors have found that the compoundsrepresented by the formulae (II), (III) and (IV) are useful as thesynthetic intermediates of the compound represented by the formula (I)which has an anti-allergic effect.

Accordingly, the object of the present invention is to provide noveltricyclic benzazepine and benzothiazepine compounds which exhibit a newtype of an anti-allergic effect and can be administered orally.

Another object of the present invention is to provide a therapeuticand/or prophylactic pharmaceutical composition against allergicdiseases.

The further object of the invention is to provide intermediate compoundswhich are important for the synthesis of the aforementioned compoundshaving the anti-allergic effect.

The tricyclic benzazepine and benzothiazepine compounds according to thepresent invention are the compounds represented by the formula (I) andpharmaceutically acceptable salts thereof. ##STR2## wherein --Z--represents

carbonyl;

a group --CR⁶ R⁷ --, wherein R⁶ and R⁷, which may be the same ordifferent, represent

hydrogen,

hydroxyl,

C₁₋₁₂ alkyl optionally substituted by halogen, hydroxyl or C₃₋₇cycloalkyl, or

C₁₋₁₂ alkoxy optionally substituted by halogen, hydroxyl or C₃₋₇cycloalkyl;

a group --(C═N--OR⁸)--, wherein R⁸ represents

hydrogen or

C₁₋₁₂ alkyl optionally substituted by C₃₋₇ cycloalkyl, or

a group --S(O)_(n) --, wherein n is an integer of 0-2;

--R represents

hydrogen;

C₁₋₆ alkyl optionally substituted by halogen, hydroxyl, C₃₋₇ cycloalkylor C₁₋₄ alkoxy;

phenyl C₁₋₄ alkyl, of which the hydrogen atoms on the benzene ring maybe optionally substituted by halogen, hydroxyl, nitro, C₁₋₄ alkyl orC₁₋₄ alkoxy; or

a protective group of the triazole group;

--R¹ represents

hydrogen;

hydroxyl;

C₁₋₁₂ alkyl optionally substituted by halogen, hydroxyl or C₃₋₇cycloalkyl;

phenyl C₁₋₄ alkyl, of which the hydrogen atoms on the benzene ring maybe optionally substituted by halogen, hydroxyl, nitro, C₁₋₄ alkyl orC₁₋₄ alkoxy;

--R², R³, R⁴ and R⁵, which may be the same or different, represent anyone of the following (a)-(v):

(a) hydrogen;

(b) halogen;

(c) hydroxyl which may be protected;

(d) cyano;

(e) nitro;

(f) thiol;

(g) formyl;

(h) C₁₋₁₂ alkyl optionally substituted by halogen, hydroxyl or C₃₋₇cycloalkyl;

(i) phenyl optionally substituted by C₁₋₄ alkyl;

(j) phenyl C₁₋₄ alkyl, of which the hydrogen atoms on the benzene ringmay be optionally substituted by halogen, hydroxyl, nitro, amino,sulfonyl, C₁₋₄ alkyl or C₁₋₄ alkoxy;

(k) C₂₋₁₂ alkenyl, which includes one or more carbon-carbon double bondsand may be optionally substituted by

(1) halogen,

(2) cyano,

(3) C₃₋₇ cycloalkyl,

(4) phenyl,

(5) a group --COR⁹, wherein R⁹ represents

hydrogen,

C₁₋₆ alkyl, or

phenyl optionally substituted by halogen, hydroxyl, C₁₋₄ alkyl or C₁₋₄alkoxy,

(6) a group --COOR¹⁰, wherein R¹⁰ represents hydrogen or C₁₋₆ alkyl,

(7) a group --CONR¹¹ R¹², wherein R¹¹ and R¹², which may be the same ordifferent, represent

(i) hydrogen,

(ii) C₁₋₆ alkyl optionally substituted by

hydroxyl;

C₁₋₄ alkoxy;

amino which may be optionally substituted by C₁₋₄ alkyl, acyl orsulfonyl;

phenyl which may be optionally substituted by halogen, hydroxyl, C₁₋₄alkyl (which may be optionally substituted by a saturated 5-7 memberedheterocyclic ring containing one or two nitrogen atoms which may beoptionally substituted by C₁₋₄ alkyl), C₁₋₄ alkoxy or carboxyl; or

a saturated or unsaturated 5-7 membered heterocyclic ring containing oneor more of oxygen atoms, nitrogen atoms or sulfur atoms, whichhetericyclic ring may be optionally substituted by C₁₋₄ alkyl or phenylC₁₋₄ alkyl or may be a bicyclic ring fused with another ring, or

(iii) phenyl, or

(iv) a saturated or unsaturated 5-7 membered heterocyclic ring which isformed by R¹¹ and R¹² together with the nitrogen atom R¹¹ and R¹²attached thereto and may further contain one or more of oxygen atoms,nitrogen atoms or sulfur atoms, which heterocyclic ring may beoptionally substituted by C₁₋₄ alkyl or phenyl C₁₋₄ alkyl or may be abicyclic ring fused with another ring;

(l) C₁₋₁₂ alkoxy optionally substituted by

(1) halogen,

(2) hydroxyl,

(3) cyano,

(4) C₃₋₇ cycloalkyl,

(5) epoxy,

(6) phenyl optionally substituted by halogen, hydroxyl, nitro, C₁₋₄alkyl or C₁₋₄ alkoxy,

(7) C₁₋₄ alkoxy,

(8) phenoxy optionally substituted by halogen, hydroxyl, C₁₋₄ alkyl,C₁₋₄ alkoxy or carboxyl,

(9) amino optionally substituted by C₁₋₄ alkyl, acyl or sulfonyl,

(10) a group --COR¹³, wherein R¹³ represents

hydrogen,

C₁₋₆ alkyl,

phenyl optionally substituted by halogen, hydroxyl, C₁₋₄ alkyl or C₁₋₄alkoxy, or

phenyl C₁₋₄ alkyl, of which the hydrogen atoms on the benzene ring maybe optionally substituted by halogen, hydroxyl, C₁₋₄ alkyl, C₁₋₄ alkoxyor carboxyl,

(11) a group --COOR¹⁴, wherein R¹⁴ represents hydrogen or C₁₋₆ alkyl,

(12) a group --CONR¹⁵ R¹⁶, wherein R¹⁵ and R¹⁶ may be the same ordifferent and represent

hydrogen,

C₁₋₆ alkyl optionally substituted by hydroxyl, C₁₋₄ alkoxy, or amino(which may be optionally substituted by C₁₋₄ alkyl, acyl or sulfonyl),or phenyl, or

(13) a saturated or unsaturated 5-7 membered heterocyclic ringcontaining one or more of oxygen atoms, nitrogen atoms or sulfur atoms,which heterocyclic ring may be optionally substituted by C₁₋₄ alkyl orphenyl C₁₋₄ alkyl, or may be a bicyclic ring fused with another ring,

(m) phenoxy optionally substituted by hydroxyl, C₁₋₄ alkyl, C₁₋₄ alkoxyor carboxyl;

(n) C₂₋₁₂ alkenyloxy optionally substituted by C₁₋₄ alkyl or phenyl;

(o) C₁₋₁₂ alkylthio optionally substituted by hydroxyl, C₃₋₇ cycloalkyl,C₂₋₄ alkenyl, C₁₋₄ alkoxy or benzyl;

(p) a group --C═N--OR²⁶, wherein R²⁶ represents

hydrogen,

C₁₋₆ alkyl,

phenyl C₁₋₄ alkyl, or

phenyl;

(q) a group --(CH₂)_(m) OR¹⁷, wherein m is an integer of 1-4, and R¹⁷represents

hydrogen,

C₁₋₆ alkyl optionally substituted by halogen, hydroxyl or C₃₋₇cycloalkyl,

phenyl C₁₋₄ alkyl, of which the hydrogen atoms of the benzene ring maybe optionally substituted by hydroxyl, C₁₋₄ alkyl or C₁₋₄ alkoxy,

phenyl, or

C₁₋₄ acyl;

(r) a group --(CH₂)_(k) --COR¹⁸, wherein k is an integer of 1-4, and R¹⁸represents

hydrogen,

C₁₋₁₂ alkyl optionally substituted by hydroxyl, C₃₋₇ cycloalkyl or C₁₋₄alkoxy, or

phenyl optionally substituted by halogen, hydroxyl, nitro, C₁₋₄ alkyl orC₁₋₄ alkoxy;

(s) a group --(CH₂)_(j) --COOR¹⁹, wherein j is an integer of 0-4, andR¹⁹ represents

hydrogen,

C₁₋₁₂ alkyl optionally substituted by halogen, hydroxyl or C₁₋₄ alkoxy,or

benzyl, of which the hydrogen atoms on the benzene ring may beoptionally substituted by C₃₋₇ cycloalkyl, C₂₋₄ alkenyl, halogen,hydroxyl, nitro, C₁₋₄ alkyl or C₁₋₄ alkoxy, or a protective group ofcarboxyl;

(t) a group --(CH₂)_(p) --NR²⁰ R²¹, wherein p is an integer of 0-4, andR²⁰ and R²¹ may be the same or different and represent

(1) hydrogen,

(2) C₁₋₆ alkyl optionally substituted by hydroxyl, amino (which may beoptionally substituted by C₁₋₄ alkyl, acyl or sulfonyl), C₃₋₇ cycloalkylor C₁₋₄ alkoxy,

(3) phenyl C₁₋₄ alkyl, of which the hydrogen atoms on the benzene ringmay be optionally substituted by halogen, hydroxyl, nitro, cyano, C₁₋₄alkyl, C₁₋₄ alkoxy or carboxyl,

(4) a group --COR²⁷, wherein R²⁷ represents

hydrogen,

C₁₋₄ alkyl optionally substituted by hydroxyl or carboxyl, or

C₃₋₇ cycloalkyl optionally substituted by hydroxyl or carboxyl, or

(5) a group --SO₂ R²⁸, wherein R²⁸ represents

C₁₋₄ alkyl,

phenyl optionally substituted by halogen, hydroxyl, nitro, cyano, C₁₋₄alkyl, C₁₋₄ alkoxy or carboxyl, or amino optionally substituted by C₁₋₄alkyl, acyl or sulfonyl, or

(6) a saturated or unsaturated 5-7 membered heterocyclic ring formed byR²⁰ and R²¹ together with the nitrogen atom R²⁰ and R²¹ attachedthereto, which heterocyclic ring may further contain one or more ofoxygen atoms, nitrogen atoms or sulfur atoms, may be optionallysubstituted by C₁₋₄ alkyl or carbonyl or may be a bicyclic ring fusedwith another ring;

(u) a group --(CH₂)_(q) --CONR²² R²³, wherein

q is an integer of 0-4, and

R²² and R²³ may be the same or different and represent

hydrogen,

C₁₋₆ alkyl (optionally substituted by C₃₋₇ cycloalkyl), C₃₋₇ cycloalkyl,

phenyl (optionally substituted by hydroxyl, C₁₋₄ alkyl or C₁₋₄ alkoxy),

sulfonyl, or

a saturated or unsaturated 5-7 membered heterocyclic ring formed by R²²and R²³ together with the nitrogen atom R²² and R²³ attached thereto,which heterocyclic ring may further contain one or more of oxygen atoms,nitrogen atoms or sulfur atoms, and may be optionally substituted byC₁₋₄ alkyl;

(v) a group --NR²⁹ R³⁰, wherein R²⁹ and R³⁰, which may be the same ordifferent, represent

(1) hydrogen,

(2) C₁₋₆ alkyl optionally substituted by

halogen,

hydroxyl,

C₁₋₄ alkoxy, or

amino which may be optionally substituted by C₁₋₄ alkyl, acyl orsulfonyl,

(3) phenyl C₁₋₄ alkyl, of which the hydrogen atoms on the benzene ringmay be optionally substituted by halogen, hydroxyl, nitro, cyano, C₁₋₄alkyl or C₁₋₄ alkoxy,

(4) a group --COR³¹, wherein R³¹ represents

hydrogen,

C₁₋₆ alkyl optionally substituted by halogen, hydroxyl,

C₁₋₄ alkyl or C₁₋₄ alkoxy, or

phenyl optionally substituted by halogen, hydroxyl, nitro, cyano, C₁₋₄alkyl or C₁₋₄ alkoxy,

(5) a group --COOR³², wherein R³² represents

C₁₋₆ alkyl, or

phenyl which may be optionally substituted by halogen, hydroxyl, nitro,cyano, C₁₋₄ alkyl or C₁₋₄ alkoxy,

(6) a group --CONR³⁴ R³⁵, wherein R³⁴ and R³⁵ may be the same ordifferent and represent

hydrogen,

C₁₋₆ alkyl optionally substituted by C₁₋₄ alkyl or amino which may beoptionally substituted by C₁₋₄ alkyl, acyl or sulfonyl, or phenyl, or

(7) a group SO₂ R³⁶, wherein R³⁶ represents

C₁₋₆ alkyl,

phenyl optionally substituted by C₁₋₄ alkyl, C₁₋₄ alkoxy or halogen, or

α- or β-naphthyl.

Furthermore, the pharmaceutical composition according to the presentinvention for the therapy and prophylaxis of allergic diseases comprisesthe compound represented by the formula (I) or a pharmacologicallyacceptable salt thereof as an effective ingredient.

The compounds represented by the formula (I) inhibit not only theimmediate responses, but also the delayed responses in allergicreactions. The compounds also exhibit the effects upon oraladministration and have continuous effects, so that these compounds areexcellent in anti-allergic effects as compared with the conventionalagents.

Furthermore, the compounds according to the present invention comprisethe compounds represented by the formulae (II), (III), (IV) and (V), andsalts thereof.

The compound according to the present invention is represented by thefollowing formula (II) and a salt thereof. ##STR3## wherein R, R², R³,R⁴ and R⁵ are as defined in the above formula (I), and R⁴¹ representshydrogen, C₁₋₆ alkyl which may be optionally substituted, or aprotective group of a carboxyl group.

Also, the compound according to the present invention is represented bythe following formula (III) and a salt 15 thereof. ##STR4## wherein R,R¹, R², R³, R⁴ and R⁵ are as defined in the above formula (I), and R⁴¹is as defined in the above formula (II).

Furthermore, the compound according to the present invention isrepresented by the following formula (IV) and a salt thereof. ##STR5##wherein R, R¹, R², R³, R⁴ and R⁵ are as defined in the above formula(I), and R⁴¹ is as defined in the above formula (II).

Furthermore, the compound according to the present invention isrepresented by the following formula (V) and a salt thereof. ##STR6##wherein R, R¹, R², R³, R⁴ and R⁵ are as defined in the above formula(I), and R⁴¹ is as defined in the above formula (II).

These compounds are useful as the synthetic intermediates of thecompound represented by the formula (I).

DETAILED DESCRIPTION OF THE INVENTION

Compounds of the formula (I)

The term "alkyl" as a part of "C₁₋₁₂ alkyl", "C₁₋₆ alkyl", "C₁₋₄ alkyl","C₂₋₁₂ alkenyl", "C₁₋₁₂ alkoxy", "C₁₋₄ alkoxy", "C₂₋₁₂ alkenyloxy", and"C₁₋₁₂ alkylthio" herein may be straight or branched.

Also, the halogen atom herein means, for example, fluorine, chlorine,bromine or iodine.

The C₁₋₆ alkyl group represented by R in the formula (I) is preferably aC₁₋₄ alkyl group. One or more of the hydrogen atoms in the alkyl groupmay be optionally substituted by a halogen atom, a hydroxyl group, aC₃₋₇ cycloalkyl group or a C₁₋₄ alkoxy group. Preferred examples of Rinclude methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, n-pentyl, 1-methyl-n-pentyl, 3-methyl-n-pentyl,4-methyl-n-pentyl, n-hexyl, cyclopropylmethyl, cyclopentylmethyl,cyclohexylmethyl, 2-cyclopentylethyl, 2-cyclohexylethyl, methoxymethyl,methoxyethyl, ethoxymethyl, 1-methoxy-n-propyl, 2-methoxy-n-pentyl,n-butoxymethyl, 2,4-dimethoxy-n-butyl, 2,4-dimethoxy-n-pentyl,2,4-dimethoxy-3-methyl-n-Pentyl, 2,4-dimethoxybutyl,2,4-dimethoxy-n-pentyl, 2,4-dimethoxy-3-methyl-n-pentyl,trifluoromethyl, 2-fluoroethyl, difluoroethyl, 2,2,2-trifluoroethyl,hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxy-n-propyl,2-hydroxy-n-propyl, 3-hydroxypropyl, 1,3-dihydroxypropyl,2,3-dihydroxypropyl, 3-hydroxy-n-butyl, 4-hydroxybutyl,2,3-dihydroxy-n-butyl, 2,4-dihydroxybutyl, 2,4-dihydroxy-n-pentyl and2,4-dihydroxy-3-methyl-n-pentyl groups.

In addition, the substituent R may represent a phenyl C₁₋₄ alkyl group.One or more of the hydrogen atoms on the benzene ring of the group maybe optionally substituted by a halogen atom, a hydroxyl group, a nitrogroup, a carboxyl group, a C₁₋₄ alkyl group or a C₁₋₄ alkoxy group. Theexamples of the substituents include preferably those at the 4-positionon the benzene ring such as a C₁₋₄ alkoxy group, a C₁₋₄ alkyl group, ahydroxyl group, a carboxyl group and a halogen atom, and those at the2-position such as a C₁₋₄ alkoxy group and a nitro group. Specificexamples of R include more preferably benzyl groups such as benzyl,4-methylbenzyl, 4-chlorobenzyl, 4-hydroxybenzyl, 4-nitrobenzyl,4-methoxybenzyl and 4-carboxybenzyl as well as a phenethyl group, a3-phenylpropyl group, and a 4-phenylbutyl group.

Furthermore, the substituent R may represent a protective group of atriazole group. The protective group includes, for example, a benzylgroup, a diphenylmethyl group, a triphenylmethyl group, a4-methoxybenzyl group, a 3,4-dimethoxybenzyl group, a3,4,5-trimethoxybenzyl group, a trimethylsilyl group and atert-butyldimethylsilyl group.

The term "C₁₋₁₂ alkyl group" represented by R¹ in the formula (I) meanspreferably a C₁₋₆ alkyl group, more preferably a C₁₋₄ alkyl group. Oneor more of the alkyl group may be optionally substituted by a halogenatom, a hydroxyl group, a C₃₋₇ cycloalkyl group. The preferred examplesof R¹ include, in addition to the examples of the "C₁₋₆ alkyl group" asregards R, long chain alkyl groups such as 1-methyl-n-hexyl,5-methyl-n-hexyl, n-heptyl, 1-methylheptyl, n-octyl, n-nonyl, n-decyl,n-undecyl and n-dodecyl.

The substituent R¹ may also represent a phenyl C₁₋₄ alkyl group. One ormore of the hydrogen atoms on the benzene ring of the group may beoptionally substituted by a halogen atom, a hydroxyl group, a C₃₋₇cycloalkyl group or a C₁₋₄ alkoxy group.

R², R³, R⁴ and R⁵ in the formula (I) independently represent any one of(a)-(v) described above.

The protective groups of the hydroxyl group (c) include, for example,groups such as acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl,benzoyl, 4-nitrobenzoyl, 3-oxobutyryl, benzyl, diphenylmethyl,triphenylmethyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, methoxymethyl,methoxyethoxymethyl, benzyloxymethyl, trimethylsilyl,tert-butyldimethylsilyl, triphenylsilyl, 2-tetrahydropyranyl andtrimethylsilylethoxymethoxy.

One or more of the hydrogen atoms of the C₁₋₁₂ alkyl group (h) may beoptionally substituted by a halogen atom, a hydroxyl group, a C₃₋₇cycloalkyl group or an amino group, which may also be optionallysubstituted by a C₁₋₄ alkyl group, an acyl group or a sulfonyl group.The acyl group include preferably a C₁₋₆ alkylcarbonyl group, morepreferably a C₁₋₄ alkylcarbonyl group, or an aromatic acyl group such asa benzoyl group, an α-naphthoyl group and a β-naphthoyl group. In thisconnection, the examples of the "acyl group" herein include preferablythose described above, unless otherwise specified.

The examples of the group (h) include preferably, in addition to thoseof the "C₁₋₆ alkyl group" specified above, long chain alkyl groups suchas 1-methyl-n-hexyl, 5-methyl-n-hexyl, n-heptyl, 1-methylheptyl,n-octyl, n-nonyl, n-decyl, n-undecyl and n-dodecyl.

Further, the phenyl group (i) may be optionally substituted by a C₁₋₄alkyl group. The examples of the group preferably include groups such asphenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl,3,4-dimethylphenyl and 3,5-dimethylphenyl.

The hydrogen atoms on the benzene ring of the phenyl C₁₋₄ alkyl group(j) may be optionally substituted by a halogen atom, a hydroxyl group, anitro group, an amino group, a carboxyl group, a sulfonyl group, a C₁₋₄alkyl group or a C₁₋₄ alkoxy group. The examples of the substituent (j)include preferably those at the 4-position on the benzene ring such as aC₁₋₄ alkoxy group, a C₁₋₄ alkyl group, a hydroxyl group, a halogen atomand a carboxyl group, and those at the 2-position such as a C₁₋₄ alkoxygroup and a nitro group. Specific examples of the phenyl C₁₋₄ alkylgroup include preferably benzyl groups such as benzyl, 4-methylbenzyl,4-chlorobenzyl, 4-hydroxybenzyl, 4-nitrobenzyl, 4-methoxybenzyl and4-carboxybenzyl as well as a phenethyl group, a 3-phenylpropyl group anda 4-phenylbutyl group.

Further, the C₂₋₁₂ alkenyl group (k) represents preferably a C₂₋₆alkenyl, more preferably C₂₋₄ alkenyl, most preferably vinyl group. Oneor more of hydrogen atoms of the alkenyl group may be optionallysubstituted by (1) a halogen atom, (2) a cyano group, (3) C₃₋₇cycloalkyl group, (4) a phenyl group, (5) a group --COR⁹, (6) a group--COOR¹⁰, or (7) a group --CONR¹¹ R¹².

R⁹ in the group --COR⁹, (5), represents a hydrogen atom, a C₁₋₆ alkyl,preferably C₁₋₄ alkyl group, or a phenyl group. In addition, one or moreof the hydrogen atoms of the phenyl group may be optionally substitutedby a halogen atom, a hydroxyl group, a C₁₋₄ alkyl group or a C₁₋₄ alkoxygroup.

R¹⁰ in the group --COOR¹⁰, (6), represents a hydrogen atom, a C₁₋₆alkyl, preferably C₁₋₄ alkyl group.

In the group --CONR¹¹ R¹², (7), R¹¹ and R¹² may be the same or differentand represent a hydrogen atom, a C₁₋₆ alkyl, preferably C₁₋₄ alkylgroup, a phenyl group or a saturated or unsaturated 5-7 memberedheterocyclic ring.

The alkyl group may be further substituted by a hydroxyl group, a C₁₋₄alkoxy group, an amino group, a phenyl group or a saturated orunsaturated 5-7 membered heterocyclic ring.

Furthermore, one or two hydrogen atoms of the amino group may beoptionally substituted by a C₁₋₄ alkyl group, an acyl group or asulfonyl group.

In addition, the phenyl group may be optionally substituted by a halogenatom, a hydroxyl group, a C₁₋₄ alkyl group, a C₁₋₄ alkoxy group or acarboxyl group. The C₁₋₄ alkyl group may be optionally substituted by asaturated 5-7 membered heterocyclic ring comprising one or two nitrogenatoms which may be optionally substituted by a C₁₋₄ alkyl group. Theexamples of the heterocyclic ring include preferably a piperidino group,a 4-piperidinyl group, a 1-pyrrolidinyl group, a piperadinyl group, a4-C₁₋₄ alkylpiperadinyl group and a morpholino group.

The saturated or unsaturated 5-7 membered heterocyclic ring means aheterocyclic ring comprising one or more of oxygen atoms, nitrogen atomand sulfur atoms, and includes preferably a pyridine ring, an imidazolering, an oxazole ring, a thiazole ring, a pyrimidine ring, a furan ring,a thiophene ring, a pyrrole ring, a pyrrolidine ring, a piperidine ring,a tetrahydrofuran ring, an oxazoline ring, a quinoline ring and anisoquinoline ring. One or more of the hydrogen atoms on the heterocyclicring may be further substituted by a C₁₋₄ alkyl group or a phenyl C₁₋₄alkyl group. The preferred examples of the phenyl C₁₋₄ alkyl groupinclude those described above. Further, the heterocyclic ring may be abicyclic ring fused with another ring.

Furthermore, R¹¹ and R¹² may form together with a nitrogen atom to whichthey are attached a saturated or unsaturated 5-7 membered heterocyclicring, which may further contain one or more oxygen atoms, nitrogen atomsor sulfur atoms and represents preferably a tetrazole ring, a thiazolering, an imidazole ring, a pyridine ring, a pyrimidine ring or apyrazine ring. One or more of the hydrogen atoms on the heterocyclicrings may be further substituted by a C₁₋₄ alkyl group or a phenyl C₁₋₄alkyl group. The preferred examples of the phenyl C₁₋₄ alkyl groupinclude those described above. Further, the heterocyclic ring may be abicyclic ring fused with another ring.

Specific examples of the C₂₋₁₂ alkenyl group, (k), include preferablyvinyl, allyl, 1-propenyl, isopropenyl, 2-methyl-1-propenyl, 1-butenyl,2-butenyl, 1,3-butanedienyl, 3-methyl-2-butenyl, 3-methyl-1-butenyl,1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-cyclopentylethenyl,2-cyclohexylethenyl, 2-cyclopentylidenemethyl, 2-cyclohexylidenemethyl,1-hexenyl, 1,5-hexadienyl, 1-heptenyl, 1,6-heptadienyl, 1-octenyl,1-nonenyl, 1-decenyl, 1-undecenyl, 1-dodecenyl, 1-methyl-1-hexenyl,2-methyl-1-hexenyl, 5,5-dimethyl-1-hexenyl,2-methoxycarbonyl-(E)-ethenyl, 2-ethoxycarbonyl-(E)-ethenyl,2-(n-propoxy)carbonyl-(E)-ethenyl, 2-isopropoxycarbonyl-(E)-ethenyl,2-(n-butoxy)-carbonyl-(E)-ethenyl, 2-isobutoxycarbonyl-(E)-ethenyl,2-(2-hydroxyethoxycarbonyl)-(E)-ethenyl,2-(2-methoxyethoxycarbonyl)-(E)-ethenyl,2-methoxycarbonyl-2-methyl-(E)-ethenyl,2-ethoxycarbonyl-2-methyl-(E)-ethenyl,2-methoxycarbonyl-2-methyl-(Z)-ethenyl,2-ethoxycarbonyl-2-methyl-(Z)-ethenyl, 2-cyano-(E)-ethenyl,2-cyano-2-methyl-(E)-ethenyl, 2-carbamoyl-(E)-ethenyl,2-(N-methylcarbamoyl)-(E)-ethenyl,2-(N,N-dimethylcarbamoyl)-(E)-ethenyl,2-(N-methyl-N-phenylcarbamoyl)-(E)-ethenyl,2-(N-(2-hydroxyethyl)-N-phenylcarbamoyl)-(E)-ethenyl,2-(N-(2-hydroxyethyl)-N-methylcarbamoyl)-(E)-ethenyl,2-(N-(2-methoxyethyl)-N-methylcarbamoyl)-(E)-ethenyl,2-(N-(2-dimethylaminoethyl)-N-methylcarbamoyl)-(E)-ethenyl,2-(N-(2-dimethylaminoethyl)-N-phenylcarbamoyl)-(E)-ethenyl,3-oxo-(E)-butenyl, 2-methyl-3-oxo-(E)-butenyl, 1(E)-pentenyl,2-methyl-l(E)-pentenyl, 2-(4-methoxybenzoyl)-(E)-ethenyl,2-(2-methoxybenzoyl)-(E)-ethenyl, 2-(4-methylbenzoyl)-(E)-ethenyl,2-(2-methylbenzoyl)-(E)-ethenyl, 2-(4-hydroxybenzoyl)-(E)-ethenyl,2-(2-hydroxybenzoyl)-(E)-ethenyl, 2-(4-chlorobenzoyl)-(E)-ethenyl,2-(2-chlorobenzoyl)-(E)-ethenyl, 2,2-bis(methoxycarbonyl)ethenyl,2,2-bis(ethoxycarbonyl)ethenyl, 2,2-dicyanoethenyl,2-methoxycarbonyl-2-cyano-(E)-ethenyl,2-methoxycarbonyl-3-oxo-(E)-butenyl,2-ethoxycarbonyl-2-cyano-(E)-ethenyl,2-ethoxycarbonyl-3-oxo-(E)-butenyl, 2-carboxy-(E)-ethenyl,2,2-bis(carboxy)ethenyl, styryl, cinnamyl,2-(N-(2-dimethylaminoethyl)carbamoyl-(E)-ethenyl,2-(N-(2-pyridyl)methylcarbamoyl)-(E)-ethenyl,2-(N-benzylcarbamoyl)-(E)-ethenyl,2-(N-(1,2,3,4-tetrazol-5-yl)carbamoyl)-(E)-ethenyl, and2-(N-(4-(4-methyl-1-piperazinyl)methyl-benzylcarbamoyl)-(E)-ethenyl.

The C₁₋₁₂ alkoxy group, (1), is preferably a C₁₋₆ alkoxy group, morepreferably a C₁₋₄ alkoxy group. The alkoxy group may be optionallysubstituted by (1) a halogen atom, (2) a hydroxyl group, (3) a cyanogroup, (4) a C₃₋₇ cycloalkyl group, (5) an epoxy group, (6) a phenylgroup, (7) a C₁₋₄ alkoxy group, (8) a phenoxy group, (9) an amino group,(10) a group --COR¹³, (11) a group --COOR¹⁴, (12) a group --CONR¹⁵ R¹⁶,or (13) a saturated or unsaturated 5-7 membered heterocyclic ring.

One or more of the hydrogen atoms on the phenyl group (6) may beoptionally substituted by a halogen atom, a hydroxyl group, a carboxylgroup, a nitro group, a C₁₋₄ alkyl group or a C₁₋₄ alkoxy group.Specific examples of the phenyl group include preferably benzyloxy,4-methylbenzyloxy, 3-methylbenzyloxy, 2-methylbenzyloxy,4-methoxybenzyloxy, 4-chlorobenzyloxy, 4-fluorobenzyloxy,4-nitrobenzyloxy, 4-hydroxybenzyloxy, 4-carboxybenzyloxy, andphenethyloxy.

In addition, one or more of the hydrogen atoms on the phenoxy group (8)may be optionally substituted by a halogen atom, a hydroxyl group, aC₁₋₄ alkyl group, a C₁₋₄ alkoxy group or a carboxyl group.

One or two hydrogen atoms of the amino group (9) may be optionallysubstituted by a C₁₋₄ alkyl group, an acyl group or a sulfonyl group.

In the group --COR¹³ (10), R¹³ represents a hydrogen atom, a C₁₋₆ alkyl,preferably C₁₋₆ alkyl group, a phenyl group or a phenyl C₁₋₄ alkylgroup.

The phenyl group may be optionally substituted by a halogen atom, ahydroxyl group, a C₁₋₄ alkyl group or a C₁₋₄ alkoxy group. The positionof the substituent, which is not particularly limited, is preferably at2- or 4-position on the phenyl ring.

Further, one or more of the hydrogen atoms on the benzene ring of thephenyl C₁₋₄ alkyl group may be optionally substituted by a halogen atom,a hydroxyl group, a C₁₋₄ alkyl group, a C₁₋₄ alkoxy group or a carboxylgroup.

In the group --COOR¹⁴ (11), R¹⁴ represents a hydrogen atom or a C₁₋₆alkyl group, preferably a C₁₋₄ alkyl group.

In the group --CONR¹⁵ R¹⁶ (12), R¹⁵ and R¹⁶, which may be the same ordifferent, represent a hydrogen atom, a C₁₋₆ alkyl, preferably C₁₋₄alkyl group, or a phenyl group. One or more of the hydrogen atoms of thealkyl group may be optionally substituted by a hydroxyl group, a C₁₋₄alkoxy group or an amino group. Furthermore, one or two hydrogen atomsof the amino group may be optionally substituted by a C₁₋₄ alkyl group,an acyl group or a sulfonyl group.

Furthermore, the saturated or unsaturated 5-7 membered heterocyclic ring(13) means a heterocyclic ring comprising one or more oxygen atoms,nitrogen atoms or sulfur atoms, and represents preferably a 5-6 memberedheterocyclic ring containing one or two nitrogen atoms such as apiperidino group, a 4-piperidinyl group, a 1-pyrrolidinyl group, apiperazinyl group or a morpholino group. One or more hydrogen atoms onthe heterocyclic ring may be further substituted by a C₁₋₄ alkyl groupor a phenyl C₁₋₄ alkyl group. Preferred examples of the phenyl C₁₋₄alkyl group preferably include those described above. The heterocyclicring may also be a bicyclic ring fused with another ring.

Specific examples of the C₁₋₁₂ alkoxy group (1) include preferably thosegroups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,isobutoxy, sec-butoxy, n-pentyloxy, n-hexyloxy, n-heptyloxy, n-octyloxy,n-nonyloxy, n-decyloxy, n-undecyloxy, n-dodecyloxy, cyclopropylmethoxy,cyclopropylethoxy, cyclopentyloxy, cyclohexyloxy, 1-methylheptyloxy,2,3-epoxypropoxy, 1-chloroheptyloxy, 2,2,2-trifluoroethoxy,methoxycarbonylmethoxy, bis(methoxycarbonyl)methoxy,2-methoxycarbonylethoxy, ethoxycarbonylmethoxy,bis(ethoxycarbonyl)methoxy, 2-ethoxycarbonylethoxy, formylmethoxy,2-formylethoxy, carbamoylmethoxy, N-methylcarbamoylmethoxy,N,N-dimethylcarbamoylmethoxy, N-methyl-N-phenylcarbamoylmethoxy,N-(2-hydroxyethyl)-N-phenylcarbamoylmethoxy,N-(2-hydroxyethyl)-N-methyl-carbamoylmethoxy,N-(2-methoxyethyl)-N-methylcarbamoylmethoxy,N-(2-dimethylaminoethyl)-N-methylcarbamoylmethoxy,N-(2-dimethylaminoethyl)-N-phenylcarbamoylmethoxy, cyanomethoxy,dicyanomethoxy, 2-cyanoethoxy, n-(2-oxo)propoxy, n-(3-oxo)butoxy,n-(3-methoxy-2-oxo)propoxy, n-(2-hydroxy-3-methoxy)propoxy, phenacyloxy,4-methoxyphenacyloxy, 4-methylphenacyloxy, 4-hydroxyphenacyloxy,4-chlorophenacyloxy, 2-methoxyphenacyloxy, 2-methylphenacyloxy,2-hydroxyphenacyloxy, 2-chlorophenacyloxy, 2-hydroxyethoxy,2-methoxyethoxy, 2-phenoxyethoxy, n-(3-hydroxy)propoxy,n-(3-methoxy)propoxy, 1,2-bis(methoxycarbonyl)-ethoxy,1,2-bis(ethoxycarbonyl)ethoxy, 1,2-dicyanoethoxy, carboxymethoxy,carboxyethoxy, 3-phenylpropoxy, 4-phenylbutoxy,2-hydroxy-4-phenylbutoxy, 2-phenoxyethoxy, 3-phenoxypropoxy,3-(N,N-dimethylamino)propoxy, and 2-(N,N-dimethylamino)ethoxy.

The phenoxy group (m) may be optionally substituted by a hydroxyl group,a C₁₋₄ alkyl group or a C₁₋₄ alkoxy group. Specific examples of thegroup preferably include phenoxy, 4-hydroxyphenoxy, 4-methylphenoxy,4-methoxyphenoxy, 3,4-dimethylphenoxy.

The a C₂₋₁₂ alkenyloxy group (n) may be optionally substituted by a C₁₋₄alkyl group or a phenyl group. Specific examples of this grouppreferably include those groups such as allyloxy,2-methyl-2-propenyloxy, 2-butenyloxy, 3-butenyloxy, 2-pentenyloxy,2-pentenyloxy, 3-pentenyloxy, 4-pentenyloxy, 2-hexenyloxy,2-heptenyloxy, 2-octenyloxy, 2-nonenyloxy, 2-decenyloxy, 2-undecenyloxy,2-dodecenyloxy, 1-methyl-2-hexenyloxy, 2-methyl-2-hexenyloxy,5,5-dimethyl-2-hexenyloxy, and cinnamyloxy.

The C₁₋₁₂ alkylthio group (o) is preferably a C₁₋₆ alkylthio group, morepreferably a C₁₋₄ alkylthio group. This alkylthio group may also beoptionally substituted by a hydroxyl group, a C₃₋₇ cycloalkyl group, aC₂₋₄ alkenyl group, a C₁₋₄ alkoxy group or a benzyl group. Specificexamples of the alkylthio group preferably include those groups such asmethylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio,isopropylthio, sec-butylthio, n-pentylthio, n-hexylthio, n-heptylthio,n-octylthio, n-nonylthio, n-decylthio, n-undecylthio, n-dodecylthio,2-hydroxyethylthio, 2-methoxyethylthio, allylthio, and benzylthio.

In the group --C═N--OR²⁶ (P), R²⁶ represents a hydrogen atom, a C₁₋₆alkyl group, preferably a C₁₋₄ alkyl group, a phenyl C₁₋₄ alkyl group ora phenyl group. Specific examples of the group preferably include thosegroups such as hydroxyiminomethoxy-imino, ethoxyimino, n-propyloxyimino,isopropyloxyimino, n-butoxyimino, isobutoxyimino, sec-butoxyimino,benzyloxyimino, 4-methoxybenzyloxyimino, 4-nitrobenzyloxyimino, andphenoxyimino.

In the group --(CH₂)_(m) OR¹⁷ (q), m is an integer of 1-4, preferably aninteger of 1 or 2, and R¹⁷ represents a hydrogen atom, a C₁₋₆ alkylgroup, preferably a C₁₋₄ alkyl group, a phenyl C₁₋₄ alkyl group or aC₁₋₄ acyl group. One or more hydrogen atoms of the alkyl group may alsobe optionally substituted by a halogen atom, a hydroxyl group or a C₃₋₇cycloalkyl group. One or more hydrogen atoms on the benzene ring of thephenyl C₁₋₄ alkyl group may also be optionally substituted by a hydroxylgroup, a C₁₋₄ alkyl group or a C₁₋₄ alkoxy group. In addition, the C₁₋₄acyl group represents those groups such as acetyl, propionyl, butyryl orvaleryl. Specific examples of the group --(CH₂)_(m) OR¹⁷ (q) preferablyinclude those groups such as hydroxymethyl, 2-hydroxyethyl,3-hydroxy-n-propyl, methoxymethyl, methoxyethyl, isopropoxymethyl,3-methoxy-n-propyl, 3-(n-pentoxy)-n-propyl, 1-hydroxy-n-propoxyethyl,2,2,2-trifluoroethoxymethyl, cyclopropylmethoxymethyl,cyclohexyloxyethyl, benzyloxymethyl, benzyloxyethyl, phenoxy-methyl,phenoxyethyl, 3-phenoxy-n-propyl, acetoxymethyl, and propionyloxymethyl.

In the group --(CH₂)_(k) COR¹⁸ (r), m is an integer of 0-4, preferably0, 1 or 2, R¹⁸ represents a hydrogen atom, a C₁₋₁₂ alkyl group,preferably a C₁₋₆ alkyl group, more preferably a C₁₋₄ alkyl group, or aphenyl group. One or more of the hydrogen atoms in the alkyl group maybe optionally substituted by a hydroxyl group, a C₃₋₇ cycloalkyl groupor a C₁₋₄ alkoxy group. The phenyl group may further be optionallysubstituted by a C₁₋₄ alkyl group or a C₁₋₄ alkoxy group. Specificexamples of the group --(CH₂)_(k) COR¹⁸ (r) preferably include C₁₋₁₂alkanoyl groups such as formyl, acetyl, propionyl, butyryl, isobutyryl,valeryl, isovaleryl, pivaloyl, pentanoyl, hexanoyl, heptanoyl, octanoyl,lauroyl, cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl,and cyclohexylcarbonyl; unsubstituted or substituted benzoyl groups suchas benzoyl, 4-methylbenzoyl, 4-methoxybenzoyl, 2-methoxybenzoyl,4-hydroxybenzoyl, 4-fluorobenzoyl, and 4-nitro-benzoyl; 2-oxopropyl,3-oxopropyl, 4-oxobutyl, 5-methyl-4-oxohexyl, and4-cyclopentyl-4-oxo-butyl.

In the group --(CH₂)_(j) COOR¹⁹ (s), j is an integer of 0-4, preferably0, 1 or 2, R¹⁹ represents a hydrogen atom, a C₁₋₁₂ alkyl group,preferably a C₁₋₆ alkyl group, more preferably a C₁₋₄ alkyl group, abenzyl group or a carboxyl group. The alkyl group may be optionallysubstituted by a halogen atom, a hydroxyl group or a C₁₋₄ alkoxy group.In addition, one or more of the hydrogen atoms on the benzene ring ofthe benzyl group may be optionally substituted by a C₃₋₇ cycloalkylgroup, C₂₋₄ alkenyl group, a halogen atom, a hydroxyl group, a nitrogroup, a C₁₋₄ alkyl group or a C₁₋₄ alkoxy group. Furthermore, theprotective groups of the carboxyl group include for example those groupssuch as methyl, ethyl, tert-butyl, benzyl, 4-methoxybenzyl,diphenylmethyl, 4-nitrobenzyl, tert-butyldimethylsilyl, triphenylsilyl,2-phenylsulfonylethyl, 2-methoxycarbonylethyl, 2-cyanoethyl, and2-trimethylsilyl-ethyl. Specific examples of the group --(CH₂)_(j)COOR¹⁹ (s) preferably include those groups such as carboxyl,methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl,n-butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl,tert-butoxycarbonyl, tert-butoxymethoxycarbonyl, n-pentyloxycarbonyl,n-hexyloxycarbonyl, n-heptyloxycarbonyl, n-octyloxycarbonyl,n-nonyloxycarbonyl, n-decyloxycarbonyl, n-undecyloxycarbonyl,n-dodecyloxycarbonyl, 2-hydroxyethoxycarbonyl,cyclopropylmethoxycarbonyl, cyclopentyloxycarbonyl,cyclohexyloxycarbonyl, 1-cyclohexyloxyethoxycarbonyl,1-chloroheptyloxycarbonyl, 2,2,2-trifluoroethoxycarbonyl,allyloxycarbonyl, carboxymethyl, methoxycarbonylmethyl,ethoxycarbonylmethyl, 2-carboxyethyl, 2-methoxycarbonylethyl,2-ethoxycarbonylethyl, benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl,4-methoxybenzyloxycarbonyl, and benzyloxycarbonylmethyl.

In the group --(CH₂)_(p) NR²⁰ R²¹ (t), p is an integer of 0-4,preferably 0, 1 or 2. R²⁰ and R²¹, which may be the same or different,represent (1) a hydrogen atom, (2) a C₁₋₆ alkyl group, (3) a phenyl C₁₋₄alkyl group, (4) a group --COR²⁷, or (5) a group --SO₂ R²⁸.

The C₁₋₆ alkyl group, which is preferably a C₁₋₄ alkyl group, may beoptionally substituted by a hydroxyl group, an amino group (which may beoptionally substituted by a C₁₋₄ alkyl group), a C₃₋₇ cycloalkyl group,or a C₁₋₄ alkoxy group.

The hydrogen atoms on the benzene ring of the phenyl C₁₋₄ alkyl group(3) may be optionally substituted by a halogen atom, a hydroxyl group, anitro group, a cyano group, a C₁₋₄ alkyl group, a C₁₋₄ alkoxy group, ora carboxyl group.

In the group --COR²⁷ of (4), R²⁷ represents a hydrogen atom, a C₁₋₄alkyl group, or a C₃₋₇ cycloalkyl group. The alkyl group may be hereinsubstituted by a hydroxyl group or a carboxyl group, and the cycloalkylgroup may be also substituted by a hydroxyl group or a carboxyl group.

In the group --SO₂ R²⁸ (5), R²⁸ represents a C₁₋₄ alkyl group, a phenylgroup or an amino group. The phenyl group may be optionally substitutedby a halogen atom, a hydroxyl group, a nitro group, a cyano group, aC₁₋₄ alkyl group, a C₁₋₄ alkoxy group or a carboxyl group. The aminogroup may also be optionally substituted by a C₁₋₄ alkyl group, an acylgroup or a sulfonyl group.

Furthermore, in the group --(CH₂)_(p) NR²⁰ R²¹, R²⁰ and R²¹ may form asaturated or unsaturated five- to seven-membered heterocyclic ringtogether with the nitrogen atom to which R²⁰ and R²¹ are attached. Theheterocyclic ring may also contain one or more oxygen atoms, nitrogenatoms or sulfur atoms. In addition, one or more of the hydrogen atoms onthe heterocyclic ring may be optionally substituted by a C₁₋₄ alkylgroup or a carbonyl group, or the heterocyclic ring may also form abicyclic ring by fusing with another ring. The heterocyclic ringpreferably includes for example those groups such as piperazino,piperidino, N-methylpiperazino, morpholino, succinimido, indolyl,4-methylindolyl, 5-methylindolyl, isoindolyl, phthalimido,4-methylphthalimido, and 1,1-dioxo-2-benzothiazolyl.

The specific examples of the group --(CH₂)_(p) NR²⁰ R²¹ (t) preferablyinclude methylamino, dimethylamino, ethylamino, diethylamino,ethylmethylamino, n-propylamino, n-butylamino, cyclohexylamino,benzylamino, 2-aminoethylamino, 2-hydroxyethylamino,2-methoxyethylamino, aminomethyl, aminoethyl, aminopropyl, aminobutyl,N-methylamino-ethyl, N,N-dimethylaminoethyl, N,N-diethylaminobutyl,acetylamino, propionylamino, butyrylamino, N-methyl-N-acetylamino,benzoylamino, 4-methylbenzoylamino, 4-methoxybenzoylamino,4-hydroxybenzoylamino, methanesulfonylamino, benzenesulfonyl-amino,p-toluenesulfonylamino, 4-methoxybenzenesulfonylamino,4-fluorobenzenesulfonyl-amino, 4-chlorobenzenesulfonylamino,naphthalene-2-sulfonylamino, and naphthalene-1-sulfonylamino.

In the group --(CH₂)_(q) CONR²² R²³ (u), q is an integer of 0-4,preferably 0, 1 or 2. R²² and R²³, which may be the same or different,represent a hydrogen atom, a C₁₋₆ alkyl group, preferably a C₁₋₄ alkylgroup, a C₃₋₇ cycloalkyl group, a phenyl group or a sulfonyl group. Thealkyl group herein may be optionally substituted by a C₃₋₇ cycloalkylgroup, and the phenyl group may also be optionally substituted by ahydroxyl group, C₁₋₄ alkyl group or a C₁₋₄ alkoxy group.

In addition, R²² and R²³ in the group --(CH₂)_(q) CONR²² R²³ (u) mayform a saturated or unsaturated five- to seven-membered heterocyclicring together with the nitrogen atom to which R²² and R²³ are attached.The heterocyclic ring may further contain one or more oxygen atoms,nitrogen atoms or sulfur atoms. Furthermore, the heterocyclic ring maybe optionally substituted by a C₁₋₄ alkyl group. Specific examples ofthe heterocyclic ring include preferably those rings similar to theheterocyclic rings formed by R²⁰ and R²¹ in the group --(CH₂)_(p) NR²⁰and R²¹ (t).

The specific examples of the group --(CH₂)_(q) CONR²² R²³ (u) includepreferably those groups such as N-methylcarbamoyl,N,N-dimethylcarbamoyl, N-ethylcarbamoyl, N-ethyl-N-methylcarbamoyl,N,N-diisopropylcarbamoyl, N-methyl-N-phenylcarbamoyl,N-tetramethylenecarbamoyl, N-pentamethylenecarbamoyl,N,N-(2-hydroxyethyl)carbamoyl, N-(1-hydroxyethyl)carbamoyl,N-cyclohexylcarbamoyl, carbamoylmethyl, 2-carbamoylethyl,N-methylcarbamoylmethyl, N-(4-methoxyphenyl)carbamoyl,N-(4-methoxyphenyl)-N-methylcarbamoyl, N-(2-methoxyphenyl)carbamoyl,N-(2-methoxyphenyl)-N-methyl-carbamoyl, N-(4-methylphenyl)carbamoyl,N-methyl-N-(4-methylphenyl)carbamoyl, N-(2-methylphenyl)carbamoyl,N-methyl-N-(2-methylphenyl)carbamoyl, N-(4-chlorophenyl)carbamoyl,N-(4-chlorophenyl)-N-methylcarbamoyl, N-(2-chlorophenyl)-carbamoyl,N-(2-chlorophenyl)-N-methylcarbamoyl, N-(4-hydroxyphenyl)carbamoyl,N-(4-hydroxyphenyl)-N-methylcarbamoyl, N-(4-methoxyphenyl)carbamoyl,N-(4-methoxyphenyl)-N-methylcarbamoylmethyl,N-(2-methoxyphenyl)carbamoylmethyl,N-(2-methoxy-phenyl)-N-methylcarbamoylmethyl,N-(4-methylphenyl)carbamoylmethyl,N-methyl-N-(4-methylphenyl)carbamoylmethyl,N-(2-methylphenyl)carbamoylmethyl,N-methyl-N-(2-methylphenyl)carbamoylmethyl,N-(4-chlorophenyl)carbamoylmethyl,N-(4-chlorophenyl)-N-methylcarbamoylmethyl,N-(2-chlorophenyl)carbamoylmethyl,N-(2-chlorophenyl)-N-methylcarbamoylmethyl,2-(N-(4-methoxyphenyl)carbamoyl)ethyl,2-(N-(4-methoxyphenyl)-N-methylcarbamoyl)ethyl,2-(N-(2-methoxyphenyl)carbamoyl)ethyl,2-(N-(2-methoxy-phenyl)-N-methylcarbamoyl)ethyl,2-(N-(4-methylphenyl)carbamoyl)ethyl, 2-(N-methyl-N-(4-methylphenyl)carbamoyl)ethyl, 2-(N-(2-methylphenyl)carbamoyl)ethyl,2-(N-methyl-N-(2-methylphenyl)carbamoyl)ethyl,2-(N-(4-chlorophenyl)carbamoyl)ethyl,2-(N-(4-chlorophenyl)-N-methylcarbamoyl)ethyl,2-(N-(2-chlorophenyl)carbamoyl)ethyl,2-(N-(2-chlorophenyl))-N-methylcarbamoyl)ethyl,N-(2-dimethylaminoethyl)-N-(4-methoxyphenyl)carbamoylmethyl,2-(N-(2-dimethylaminoethyl)-N-(4-methoxyphenyl)-carbamoyl)ethyl,N-(2-dimethylaminoethyl)-N-(2-methoxyphenyl)carbamoyl)methyl,2-(N-(2-dimethylaminoethyl)-N-(2-methoxyphenyl) carbamoyl)ethyl,N-(2-dimethylamino-ethyl)-N-(4-methylphenyl)carbamoylmethyl,2-(N-(2-dimethylaminoethyl)-N-(4-methylphenyl)carbamoyl)ethyl,N-(2-dimethylaminoethyl)-N-(2-methylphenyl)carbamoyl-methyl, and2-(N-(2-dimethylaminoethyl)-N-(2-methylphenyl)carbamoyl)ethyl.

In the group --NR²⁹ R³⁰ (v), R²⁹ and R³⁰, which may be the same ordifferent, represent (1) a hydrogen atom, (2) a C₁₋₆ alkyl group,preferably a C₁₋₄ alkyl group, (3) a phenyl C₁₋₄ alkyl group, (4) agroup --COR³¹, (5) a group --COOR³², or (6) a group --CONR³⁴ R³⁵.

The alkyl group (2) herein may be optionally substituted by a halogenatom, a hydroxyl group, a C₁₋₄ alkoxy group or an amino group, which mayalso be optionally substituted by a C₁₋₄ alkyl group, an acyl group or asulfonyl group.

Further, the hydrogen atom on the benzene ring of the phenyl C₁₋₄ alkylgroup (3) may be optionally substituted by a halogen atom, a hydroxylgroup, a nitro group, a cyano group, a C₁₋₄ alkyl group, or a C₁₋₄alkoxy group.

In the group --COR³¹ (4), R³¹ represents a hydrogen atom, a C₁₋₆ alkylgroup, preferably a C₁₋₄ alkyl group, or a phenyl group. The alkyl groupmay be optionally substituted by a halogen atom, a hydroxyl group, aC₁₋₄ alkyl group or a C₁₋₄ alkoxy group. Further, the phenyl group mayalso be optionally substituted by a halogen atom, a hydroxyl group, anitro group, a cyano group, a C₁₋₄ alkyl group, or a C₁₋₄ alkoxy group.

In the group --COOR³² (5), R³² represents a C₁₋₆ alkyl group, preferablya C₁₋₄ alkyl group, or a phenyl group. The phenyl group may beoptionally substituted by a halogen atom, a hydroxyl group, a nitrogroup, a cyano group, a C₁₋₄ alkyl group, or a C₁₋₄ alkoxy group.

In the group --CONR³⁴ R³⁵, R³⁴ and R³⁵, which may be the same ordifferent, represent a hydrogen atom, a C₁₋₆ alkyl group, preferably aC₁₋₄ alkyl group, or a phenyl group. The alkyl group may be optionallysubstituted by a C₁₋₄ alkyl group or an amino group. The amino group mayalso be optionally substituted by a C₁₋₄ alkyl group, an acyl group or asulfonyl group.

The specific examples of the group --NR²⁹ R³⁰ (v) preferably includethose groups such as amino, N-methylamino, N,N-dimethylamino,N-methylamino, N,N-diethylamino, N-ethyl-N-methylamino, N-benzylamino,N-(4-methoxybenzyl)amino, N-(4-nitrobenzyl)amino,N-(2,4-dimethoxybenzyl)amino, N,N-dibenzylamino,N,N-bis(4-nitrobenzyl)amino, N,N-bis(4-dimethoxybenzylamino),N,N-triphenylmethylamino, formylamino, chloroacetylamino,trifluoroacetylamino, trichloroacetylamino, N-(p-toluoyl)amino,N-(4-methoxybenzoyl)amino, N-(4-hydroxybenzoyl)amino,N-(2-methoxy-benzoyl)amino, N-(2-hydroxybenzoyl)amino,tert-butoxycarbonylamino, benzyloxycarbonylamino,2-trichloroethoxycarbonylamino, 2-trimethylsilylethoxycarbonyl-amino,naphthalene-1-sulfonylamino, and naphthalene-2-sulfonylamino.

Furthermore, in the compound according to the present invention, theremay be tautomers derived from the triazol ring and cis-trans isomersderived from the alkenyl group of the substituent. Either isomers andmixtures thereof are also encompassed within the present invention.

A preferred class of compounds of formula(I) according to the presentinvention include

a group wherein Z represents a carbonyl group, R represents a hydrogenatom, and R¹, R², R³, R⁴ and R⁵ represent a hydrogen atom or (h) theC₁₋₁₂ alkyl group;

a group wherein Z represents a carbonyl group, R and R¹ represent ahydrogen atom, and R², R³, R⁴ and R⁵ represent a hydrogen atom or (1)the C₁₋₁₂ alkoxy group;

a group wherein Z represents a carbonyl group, R, R¹, R² and R⁵represent a hydrogen atom, R³ and R⁴ represent a hydrogen atom or (h)the C₁₋₁₂ alkyl group;

a group wherein Z represents a carbonyl group, R, R¹, R² and R⁵represent a hydrogen atom, R³ and R⁴ represent a hydrogen atom or (k)the C₂₋₁₂ alkenyl group;

a group wherein Z represents a carbonyl group, R, R¹, R² and R⁵represent a hydrogen atom, and R³ and R⁴ represent a hydrogen atom or(1) the C₁₋₁₂ alkoxy group;

a group wherein Z represents a carbonyl group, R, R¹, R², R⁴ and R⁵represent a hydrogen atom, R³ represents (h) the C₁₋₁₂ alkyl group;

a group wherein Z represents a carbonyl group, R, R¹, R², R⁴ and R⁵represent a hydrogen atom, R³ represents (k) the C₂₋₁₂ alkenyl group;

a group wherein Z represents a carbonyl group, R, R¹, R², R⁴ and R⁵represent a hydrogen atom, and R³ represents (l) the C₁₋₁₂ alkoxy group;

a group wherein Z represents a carbonyl group, R, R¹, R², R³ and R⁵represent a hydrogen atom, and R⁴ represents (k) the C₂₋₁₂ alkenylgroup;

a group wherein Z represents a carbonyl group, R, R¹, R², R³ and R⁵represent a hydrogen atom, and R⁴ represents (l) the C₁₋₁₂ alkoxy group;

a group wherein Z represents a carbonyl group, R³ and R⁴ represent (r)the group --(CH₂)_(k) COR¹⁸, (t) the group --(CH₂)_(p) NR²⁰ R²¹, (u) thegroup --(CH₂)_(q) NR²² R²³ or (v) the group --NR²⁹ R³⁰ ;

a group wherein Z represents a group --CR⁶ R⁷ --, R and R¹ represent ahydrogen atom, R², R³, R⁴ and R⁵ represent a hydrogen atom, (h) theC₁₋₁₂ alkyl group, (k) the C₂₋₁₂ alkenyl group, or (l) the C₁₋₁₂ alkoxygroup, the compound being preferably the one wherein both of R⁶ and R⁷represent a hydrogen atom, or either one represents a hydrogen atom andthe other represents (h) the C₁₋₁₂ alkyl group or (l) the C₁₋₁₂ alkoxygroup;

a group wherein Z represents a group --(C═N--OR⁸)--, wherein R⁸represents a hydrogen atom or a C₁₋₁₂ alkyl group, R and R¹ represents ahydrogen atom, and R², R³, R⁴ and R⁵ represent a hydrogen atom, (h) theC₁₋₁₂ alkyl group, (k) the C₂₋₁₂ alkenyl group, or (l) the C₁₋₁₂ alkoxygroup; and

a group wherein Z represents a group --S(O)_(n), R and R¹ represent ahydrogen atom, and R², R³, R⁴ and R⁵ represent a hydrogen atom, (h) theC₁₋₁₂ alkyl group, or (l) the C₁₋₁₂ alkoxy group.

The preferred compounds include particularly

7-methyl-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c! 1!benzazepine,

7-ethyl-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c! 1!benzazepine,

7-methoxy-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c! 1!benzazepine,

7-ethoxy-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c! 1!benzazepine,

8-methyl-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c! 1!benzazepine,

8-methoxy-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c! 1!benzazepine,

8-ethoxy-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c! 1!benzazepine,

7-cyanomethoxy-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c! 1!benzazepine,

7-methoxycarbonylmethoxy-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine,

8-methoxycarbonylmethoxy-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine,

7-(4-methoxybenzoylmethoxy)-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine,

7-acetonyloxy-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c! 1!benzazepine,

7-(2-methoxycarbonyl-(E)-ethenyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine,

7(2-methoxycarbonylethyl)-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine,

7-(2-carboxy-(E)-ethenyl)-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine,

7-(2-cyano-(E)-ethenyl)-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine,

7-(3-oxo-(E)-butenyl)-4(5H),10-dioxo-H-1,2,3-triazolo 4,5-c!1!benzazepine,

7,8-dimethyl-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c! 1!benzazepine,

7,8-dimethoxy-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c! 1!benzazepine,

7-methyl-8-methoxy-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine,

7-(2-methoxycarbonyl-2-methyl-(E)-ethenyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine,

7-(2-(4-methoxybenzoyl)-(E)-ethenyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine,

7-(2-(N-benzylcarbamoyl)-(E)-ethenyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine,

4(5H),10-dioxo-7-(2-(N-(2-pyridyl)methylcarbamoyl)-(E)-ethenyl)-1H-1,2,3-triazolo4,5-c! 1!benzazepine,

7-(N-(4-(4-methyl-1-piperazinyl)methylbenzylcarbamoyl)-(E)-ethenyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine,

4(5H),10-dioxo-7-(2-(N-(1H-tetrazol-5-yl)carbamoyl)-(E)-ethenyl)-1H-1,2,3-triazolo4,5-c! 1!benzazepine,

7-(hydroxyimino)methyl-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine,

7-(methoxyimino)methyl-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine,

7-(benzyloxyimino)methyl-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine,

7-(N-acetyl-N-propylaminomethyl)-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine,

7-(N-(3-carboxypropanoyl)-N-propylaminomethyl-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine,

7-(N-benzylaminomethyl)-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine,

7-(2-(N,N-dimethylamino)ethylaminomethyl-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine,

7-(N-(4-carboxybutyryl)aminomethyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine,

7-(N-acetylaminomethyl)-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine,

7-(N-methanesulfonylaminomethyl)-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine,

7-(N-benzenesulfonylaminomethyl)-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine,

4(5H), 10-dioxo-7-(3-phenoxypropoxy)-1H-1,2,3-triazolo 4,5-c!1!benzazepine,

4(5H), 10-dioxo-7-(3-phenylpropoxy)-1H-1,2,3-triazolo 4,5-c!1!benzazepine,

4(5H), 10-dioxo-7-(2-oxo-4-phenylbutoxy)-1H-1,2,3-triazolo 4,5-c!1!benzazepine,

7-(2-hydroxy-4-phenylbutoxy)-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine,

7-(3-(4-benzyl-1-piperazinyl)propoxy)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine,

4(5H),10-dioxo-7-(3-(1-piperidinyl)propoxy)-1H-1,2,3-triazolo 4,5-c!1!benzazepine,

7-(3-(N,N-dimethylamino)propoxy)-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine,

8-(2-methoxyethoxy)-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine,

8-(2-methoxyphenacyloxy)-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine,

7-formyl-5-hydroxy-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine,

4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c! 1!benzazepine,

6-methyl-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c! 1!benzazepine,

7-methyl-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c! 1!benzazepine,

8-methyl-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c! 1!benzazepine,

9-methyl-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c! 1!benzazepine,

10(9H)-oxo-3H-1,2,3-triazolo 4,5-b! 1,5!benzothiazepine,

10(9H)-oxo-3H-1,2,3-triazolo 4,5-b! 1,5!benzothiazepine 4-oxide,

10(9H)-oxo-3H-1,2,3-triazolo 4,5-b! 1,5!benzothiazepine 4,4-dioxide,

7-(N-(4-fluorobenzenesulfonyl)aminomethyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine,

7(N-(4-chlorobenzenesulfonyl)aminomethyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c!1!benzazepine,

7-(2-methoxyphenacyloxy)-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine,

7-(4-chlorophenacyloxy)-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine,

4(5H),10-dioxo-7-(2-phenoxyethoxy)-1H-1,2,3-triazolo 4,5-c!1!benzazepine,

8-(4-methoxyphenacyloxy)-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine, and

7-(4-methylbenzoyl)amino-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine.

The compound according to the present invention can be formed into apharmacologically acceptable salt thereof. Such salts includemedicinally acceptable non-toxic salts, preferably alkali metal oralkaline earth metal salts such as a sodium salt, a potassium salt or acalcium salt; hydrogen halide salts such as a hydrofluoride, ahydrochloride, a hydrobromide or a hydroiodide; inorganic acid saltssuch as a nitric acid salt, a perchloric acid salt, a sulfuric acid saltor a phosphoric acid salt; lower alkylsulfonic acid salts such as amethanesulfonic acid salt, a trifluoromethanesulfonic acid salt or anethanesulfonic acid salt; arylsulfonic acid salts such as abenzenesulfonic acid salt or a p-toluenesulfonic acid salt; organic acidsalts such as a fumaric acid salt, a succinic acid salt, a citric acidsalt, a tartaric acid salt, an oxalic acid salt or a maleic acid salt;amino acid salts such as a glutamic acid salt or an aspartic acid salt.

Preparation of the compound of the formula (I)

The compound according to the present invention can be synthesizedaccording to the following reaction schemes (A)-(E).

In this context, the compound (I) in the following reaction schemes canbe represented as

the compound (Ia) where Z represents a carbonyl group,

the compound (Ib) where Z represents a group CR⁶ R⁷,

the compound (Ic) where Z represents a group --(C═N-OR⁸)--, and

the compound (Id) where Z represents a group S(O)_(n).

In addition, the compound (I) in the following reaction schemes shouldbe represented as

the compound (Id-1) where Z represents a sulfide group (n=0),

the compound (Id-2) where Z represents a sulfoxide group (n=1), and

the compound (Id-3) where Z represents a sulfone group (n=2).

In the above formulae, R, and R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R⁴¹have the same meanings as defined above. ##STR7## Reaction scheme (A)

The compound of the formula (Ia) can be obtained by cyclizing thecompound (III) and removing the protective groups, if necessary. Thecompound (III) can be also obtained by oxidizing the compound (II) andthen reducing it. The procedures are described in detail below.

(A-1) Synthesis of the compound (II):

The compound represented by the formula (II) can be synthesized from thesubstituted or unsubstituted 2-nitrobenzaldehyde of the formula (VI) asa starting material.

The compound (VI) and an alkali metal salt of a propiolic acid esterwhich is prepared easily by the conventional method with the propiolicacid ester can be reacted in an inert solvent such as toluene,dimethylformamide, ether, tetrahydrofuran or a mixture thereof at areaction temperature of -78°-30° C., preferably -78°-0° C., for 0.1-24hours, usually 0.1-1 hour, to give the compound (VII).

The compound (VII) can be next reacted with the azide represented by theformula R--N₃ (VIII), wherein R has the same meanings as defined above,in an inert solvent such as toluene, dimethylformamide,dimethylsulfoxide, an organic acid ester, for example ethyl acetate,butyl acetate or ethyl propionate, dioxane or a mixture thereof at areaction temperature of 0°-150° C., preferably 30°-110° C., for 1-48hours, usually 5-24 hours to give the compound represented by theformula (II).

The azide compound can be prepared according to the methods, forexample, described in J. R. E. Hoover and A. R. Day, J. Amer. Chem.Soc., 78, 5832 (1956), D. R. Buckle and C. J. M. Rockell, J. Chem. Soc.Perkin I, 1982, 627, B. Loubinoux, J.-L. Colin and S. Tabbache, J.Heterocyclic Chem., 21, 1669 (1984), I. F. Cottrell, D. Hands, P. G.Houghton, G. R. Humphrey and S. H. B. Wright, J. Heterocyclic Chem., 28,301 (1991).

Further, the alkali metal of the alkali metal salt of the propiolic acidester used in the reaction with the compound (VI) described aboveincludes for example lithium, sodium and potassium, preferably lithium.

The compound (II) thus obtained, which is a mixture of the isomers withrespect to the triazole portion, i.e. isomers with respect to R, may beused for the subsequent reaction without isolating each of the isomers.

(A-2) Synthesis of the compound (III):

The compound represented by the formula (III) can be easily obtained byoxidizing the compound (II) obtained in the preceding step (A-1) to givethe compound (IX), which is further subjected to reduction reaction.

In the oxidation reaction, there can be used a metal oxidizing agentsuch as chromic acid or permanganic acid, catalytic air oxidation, ororganic oxidation with dichlorodicyanobenzoquinone (DDQ). There can bepreferably used the oxidation with manganese dioxide in a methylenechloride solution at room temperature and the oxidation withdimethylsulfoxide in a methylene chloride solution, for example in adimethylsulfoxide-oxalyl chloride-triethylamine system at a temperatureof -78°-25° C.

The mixture of the isomers with respect to the triazole moiety in thestep of the compound (IX), i.e. the isomers with respect to R, can beseparated from each other, or it may be used without separation in thesubsequent reaction to give the compound (I).

The compound (IX) can be next hydrolyzed with an alcoholic solution ofsodium hydroxide, potassium hydroxide or lithium hydroxide to form acorresponding carboxylic acid or without forming the carboxylic acidderivative and subjected to reduction reaction to give the aminocompound of the formula (III) wherein R¹ ═H.

In this reduction reaction, there can be used the conventional catalyticreduction, in which a nickel catalyst or a palladium catalyst ispreferably used, and a solvent such as ethyl acetate, an alcoholicsolvent such as ethanol, or water is preferably used solely or as anadmixture thereof, or a reduction method with a metal such as iron orzinc, for example the reduction reaction in a zinc-acetic acid system.

The reduction can be carried out at a temperature of 10°-100° C. for0.1-10 hours, if necessary by reacting an alkylating agent, i.e. anN-alkylating agent, in the presence of a base to give the compound(III).

The N-alkylation can be also conducted by the following method. Thecompound (III), wherein R¹ ═H, R⁴¹ =a C₁₋₆ alkyl group or a protectivegroup of a carboxyl group, is reacted with methyl chlorocarbonate orbenzyl chlorocarbonate, i.e. carboxybenzyl chloride under theconventional condition to form a carbamic acid ester, which with thealkylating agent is reacted in the presence of a base.

Then, acid hydrolysis, alkaline hydrolysis or catalytic reduction isconducted under the conventional condition to lead the carbamic acidester to the aniline derivative (III) wherein R¹ =a C₁₋₁₂ alkyl group,R⁴¹ =a C₁₋₆ alkyl group or a protective group of a carboxyl group.

As the alkylating agent in the N-alkylation reaction, there can be usedthe conventional alkyl halide or alkyl ester of an sulfonic acid.Further, as the base, there can be used n-butyllithium, sodium hydride,potassium hydride, sodium hydroxide or potassium hydroxide. As thereaction solvent, tetrahydrofuran, dioxane, toluene, dimethylformamide,and dimethylsulfoxide are used solely or as a mixed solvent.

While the reaction temperature and the reaction period may beappropriately determined in consideration of the combination of thealkylating agent, a base and a reaction solvent, these conditions aregenerally in the range of -25°-50° C. and 1-24 hours, for example at 20°C. for 14 hours in the methyl iodide/sodium hydride/dimethylformamidesystem.

(A-3) Synthesis of the compound (Ia):

The compound (III) obtained in the preceding step (A-2) can be cyclizedunder the following condition and, if necessary, subjected toN-alkylation or to deprotecting reaction to give the compound (Ia).

Cyclization:

When the compound (III) is a carboxylic acid (R⁴¹ ═H), cyclization canbe conducted with a reagent for dehydrative cyclization used for theconventional cyclopeptide synthesis, for example a reagent for activeester formation such as N,N'-dicyclohexyl-carbodiimide (DCC), a pyridinederivative and a phosphate derivative, or a dehydrating agent such asthionyl chloride and phosphorus oxychloride. The reaction conditionincluding the reaction solvent, the temperature and the reaction periodmay be appropriately determined in consideration of the dehydrating andcyclizing agent used or the like. When 2-fluoro-1-methylpyridiniump-toluenesulfonate/tributylamine/3,4-dihydro-2H-pyrido1,2-a!pyrimidin-2-one is used as the dehydrating and cyclizing agent,the reaction is preferably conducted in a tetrahydrofuran or methylenechloride solvent under the condition at -10°-50° C. for 0.5-24 hours.

When the compound (III) is an ester wherein R⁴¹ =a C₁₋₆ alkyl group or aprotective group of a carboxyl group, it can be reacted with a strongbase such as sodium hydride, potassium hydride, sodium methoxide, sodiumethoxide or potassium tert-butoxide in an inert solvent, for example analcohol such as methanol, ethanol or isopropanol, toluene,dimethylformamide, dimethylsulfoxide, dioxane, tetrahydrofuran or amixture thereof at a reaction temperature of 0°-100° C. for 1-48 hours,usually 5-24 hours to give the compound (Ia).

N-alkylation:

When the cyclized compound (Ia) is the compound wherein R¹ ═H, it can bereacted with an alkylating agent in the presence of a base, ifnecessary, prior to removing the protective group of a functional groupsuch as triazole to give the compound (Ia) wherein R¹ is a C₁₋₁₂ alkylgroup.

The N-alkylation can be carried out under the same reaction condition asin the alkylation reaction of the compound (III) described above.

Deprotecting reaction:

The compound (Ia), wherein the triazole group is protected, can bedeprotected by the conventional method as follows. For example, when theprotective group of the compound (Ia) is a group such as benzyl,diphenylmethyl, triphenylmethyl, 4-methoxybenzyl,3,4,5-trimethoxybenzyl, benzyloxymethyl or trimethylsilyl, the compound(Ia) is reacted with an mineral acid such as dilute hydrochloric acid ordilute sulfuric acid or an organic acid such as acetic acid ortrifluoroacetic acid solely or as a dilution with an inert solvent suchas methylene chloride or toluene according to the methods described byD. R. Buckle and C. J. M. Rockell in J. Chem. Soc. Perkin I, 1982, 627or by F. E. Nielsen and E. B. Pedersen in J. Heterocyclic Chem., 22,1693 (1985). The protective group can be removed usually under thecondition at 15°-80° C. for 1-10 hours to give the compound (Ia, R═H).

Reaction scheme (B)

According to the second method of the present invention, the method ofthe reaction scheme (B), the compound (I) can be prepared by thefollowing method.

The compound (Ia) can be obtained by cyclizing the compound (IV), and ifnecessary removing the protective group. The compound (IV) can beobtained by subjecting the aniline derivative (X) and the triazolederivative (XI) to condensation reaction. The procedures are describedin detail below.

(B-1) Synthesis of the compound (IV):

The compound represented by the formula (IV) can be prepared by reactingthe aniline derivative (X) and the triazole derivative (XI) in an inertsolvent such as toluene, tetrahydrofuran, methylene chloride, an aceticacid ester or dimethylformamide in the presence of an organic base suchas pyridine or triethylamine and a dehydrating agent such as thionylchloride or phosphorus oxychloride at -10°-25° C. for 0.5-5 hours.

The compound (IV) can be prepared by condensing the aniline derivative(X) and a corresponding acid chloride which can be prepared by theconventional method in the presence of an organic base or an inorganicbase such as an alkali carbonate or an alkali bicarbonate.

The compound (XI) used herein can be prepared by hydrolyzing the adductof the azide compound (VIII) an acetylene dicarboxylic acid estersynthesized according to the method described by B. Loubinoux, J.-L.Colin and S. Tabbache in J. Heterocyclic Chem., 21, 1669 (1984) with anequimolar alkali hydroxide in an alcoholic acid at -10°-25° C. for 0.5-2hours.

The compound (IV) can be converted into the compound (IV), wherein R⁴¹═H, by ester hydrolysis, which is generally a reaction with an alkalihydroxide such as sodium hydroxide in an aqueous alcohol solution or amixed solution of tetrahydrofuran and water.

(B-2) Synthesis of the compound (Ia):

The compound (Ia) can be obtained by cyclization of the compound (IV).The compound (Ia) can be synthesized as a cyclization product bytreating the compound (IV), wherein R⁴¹ ═H, with a reagent fordehydrative cyclization such as polyphosphoric acid (PPA), apolyphosphoric acid ester (PPE) or concentrated sulfuric acid orsubjecting the amidocarboxylic acid to the intramolecularFriedel-Crafts' reaction via the acid halide.

The solvent which can be used preferably includes inert solvents, forexample, carbon disulfide, a benzene type solvent such as benzene ornitrobenzene, a halogenated hydrocarbon solvent such as carbontetrachloride solely or as a mixed solvent.

As the acid halide, there can be used an acid chloride or an acidbromide which can be prepared in the conventional method, and as thereagent for the intramolecular Friedel-Crafts' reaction there can beused for example a Lewis acid such as anhydrous aluminum chloride oranhydrous tin chloride.

The reaction temperature and time may be appropriately determined inconsideration of the combination of the acid halide, the Lewis acid andthe solvent, and it is preferably in the range of 0°-80° C. and 0.5-24hours.

It is also possible to convert the compound (Ia) obtained into anN-alkyl derivative by treating the compound in the same manner as in theN-alkylation reaction described in the reaction scheme (A-3).

Furthermore, in the case of removing the protective group, the compound(Ia, R═H) can be obtained by the deprotecting reaction in the samemanner as described in the reaction scheme (A-3).

Reaction scheme (C):

According to the third method illustrated in reaction scheme (C), thecompound (I) can be synthesized in the following method.

The compound of the formula (Ib) can be obtained by reducing, and ifnecessary alkylating, the compound (Ia), or by reacting it with anorganic metal compound and if necessary removing the protective group.The procedures are described in detail below.

The compound (Ib) can be obtained by reducing the compound (Ia) preparedby the methods described in the preceding reaction schemes (A) or (B)with a reducing agent which is generally used for the reduction of acarbonyl group in an inert solvent, preferably sodium borohydride (inwater, an alcohol, an aqueous alkali hydroxide solution, or a mixedsolution thereof), lithium borohydride (in an ether solvent such astetrahydrofuran or in toluene), or lithium aluminum hydride (in an ethersolvent such as tetrahydrofuran).

The reaction temperature and time may be appropriately determined inconsideration of the reducing agent, solvent and the combinationthereof, and the reaction can be generally completed at -78°-50° C.within 0.5-24 hours.

The compound (Ib) thus obtained, wherein Z=CHOH, can be converted, ifnecessary, to the compound (Ib) wherein R⁶ represents a hydrogen atom,and R⁷ represents a C₁₋₁₂ alkoxy group by reacting with an alkylatingagent in the presence of a base.

As the alkylating agent, there can be used a generally used alkyl halideor an alkyl ester of a sulfonic acid, and as the base, there can be usedfor example n-butyllithium, sodium hydride, potassium hydride, sodiumhydroxide or potassium hydroxide. As the reaction solvent, there can beused for example tetrahydrofuran, dioxane, toluene, dimethylformamide ordimethylsulfoxide solely or as a mixed solvent thereof.

The reaction temperature and time may be appropriately determined inconsideration of the combination of the alkylating agent, the base andthe reaction solvent, and the reaction generally requires the conditionof -25°-50° C. and 1-24 hours (for example at 20° C. for 8 hours in thesystem of methyl iodide/sodium hydride/dimethylformamide.

Furthermore, compound (Ib) wherein R⁶ represents a hydroxyl group and R⁷represents a C₁₋₁₂ alkyl group can be obtained by reacting the compound(Ia) with the conventional Grignard reagent or an organic metal compoundsuch as an alkyllithium in an inert solvent such as a hydrocarbonsolvent, for example ether, tetrahydrofuran or a mixture thereof at-100°-50° C., preferably -78°-20° C. for 0.5-24 hours.

When the protective group is removed, it is possible to prepare thecompound (Ib) by conducting the deprotection reaction in the same manneras described in the reaction scheme (A-3).

Reaction scheme (D):

According to the fourth method of the present invention illustrated inreaction scheme (D), the compound (I) can be synthesized in thefollowing method.

The compound represented by the formula (Ic) can be obtained by reactingthe compound (Ia) with an amine compound (H₂ N--OR⁸), and, if necessary,removing the protective group.

The compound (Ic) can be obtained by reacting the compound (Ia) with theamine compound (H₂ N--OR⁸) in an inert solvent such as methanol,ethanol, tetrahydrofuran, dioxane, dimethylformamide, dimethylsulfoxide,chloroform or methylene chloride solely or as a mixed solvent thereof ata reaction temperature of -78°-80° C., preferably -25°-50° C. generallyfor 0.5-24 hours, preferably 0.5-6 hours.

The amine compound wherein R⁸ represents a C₁₋₁₂ alkyl group for use inthe oxime formation reaction can be generally prepared easily byalkylating N-hydroxyphthalimide followed by the dephthaloylation.

When the compound (Ic) obtained is a hydroxime compound (R⁸ ═H), thecompound (Ic, R⁸ =a C₁₋₁₂ alkyl group) can be obtained by carrying outthe alkylation reaction in the presence of a base according tonecessity.

These alkylation reactions can be conducted under the same reactioncondition as in the O-alkylation reaction in the preceding reactionscheme (C).

Furthermore, in the case of removing the protective group, it ispossible to prepare the compound (Ic) by conducting the deprotectionreaction in the same manner as described in the reaction scheme (A-3).

Reaction scheme (E):

Furthermore, according to the fifth method of the present inventionillustrated in reaction scheme (E), the compound (I) can be synthesizedin the following method.

The compound of the formula (Id) can be prepared by cyclizing thecompound (V) and oxidizing the product to remove the protective group.

Furthermore, the compound (V) can be prepared by condensing themercaptaniline derivative (XII) and the triazole derivative (XIII). Theprocedures are described in detail below.

(E-1) Synthesis of the compound (V):

The compound (V) can be prepared by subjecting the compound (XII) andthe compound (XIII) condensation reaction in the presence of a baseaccording to for example the method described by D. R. Buckle, C. J. M.Rockell, H. Smith and B. A. Spicer in J. Med. Chem., 27, 223 (1984).

In this reaction, not only sodium hydride but also sodium hydroxide,potassium hydroxide, sodium methoxide, sodium ethoxide and the like canbe used as the base. As the reaction solvent, not only dimethylformamidedescribed in the literature but also an alcohol such as methanol andethanol, tetrahydrofuran, water and a mixed solvent thereof can be used.The reaction temperature and the reaction period are preferably at-10°-60° C. for 0.5-24 hours.

The compound (XIII) used herein can be prepared easily according to themethod described in D. R. Buckle and C. J. M. Rockell, J. Chem. Soc.Perkin I, 1982, 627; J. Chem. Research (S), 1982, 292.

(E-2) Synthesis of the compound (Id):

The compound represented by the formula (Id) can be synthesized bysubjecting the compound (V) prepared in the preceding step (E-1) tocyclization reaction under the same reaction condition as described inthe preceding reaction scheme (A-3) to give the compound (Id-1), whichis oxidized to remove the protective group, if necessary.

The sulfide derivative (Id-1) of the cyclized compound can be convertedto the sulfoxide compound (Id-2) and the sulfone compound (Id-3) by theconventional oxidation reaction.

The oxidizing agent used preferably include organic peracids in an inertsolvent such as peracetic acid (for example, in acetic acid), perbenzoicacid or m-chloroperbenzoic acid (for example, in a halogenatedhydrocarbon solvent such as methylene chloride, chloroform or1,2-dichloroethane), or inorganic oxidizing agents such as sodiumperiodate (for example, in an aqueous alcoholic solution such asmethanol) and potassium permanganate (for example, in an aqueous aceticacid solution).

It is possible to obtain the sulfoxide compound (Id-2) by reacting thecompound (Id-1) with the oxidizing agent in an amount of 1-1.5equivalents and the sulfone compound (Id-3) with the oxidizing agent inan amount of 2-3.5 equivalents.

The Reaction temperature and time of the oxidation may be appropriatelydetermined in consideration of the aimed product of the sulfoxide or thesulfone and the combination of the oxidizing agent and the solvent, thereaction is preferably conducted at -10°-90° C., preferably 0°-60° C.,for 0.5-48 hours.

Furthermore, it is possible to prepare the compound (Id, R═H) bysubjecting the compound (Id-1), (Id-2) or (Id-3) to deprotectionreaction to remove the protective group.

In each of the above reaction schemes (A)-(E), when R², R³, R⁴ or R⁵represent independently an amino group, a hydroxyl group or a carboxylgroup, the corresponding compound can be subjected to the respectivedeprotection reactions in an appropriate reaction step, preferablyaround the reaction step for removing the protective group of thetriazole group to produce the compound represented by the formula (I).In this context, the deprotection can be conducted according to theconventional method by selecting a deprotecting reagent with respect toeach of the protective groups of the amino group, the hydroxyl group orthe carboxyl group and with respect to the reaction step according tothe conventional method and by using the deprotecting reagentappropriately.

The compound of the formula (I) which is synthesized by the abovemethods can be purified by the conventional purification methods such asrecrystallization, reprecipitation, extraction with solvent, silica gelcolumn chromatography, or column chromatography with an adsorptiveresin.

Use of the compound/pharmaceutical composition

The compound represented by the formula (I) has an anti-allergicactivity.

Thus, the compound according to the present invention is useful for thetherapy and prophylaxis of diseases associated with allergy.

Specifically, the compound according to the present invention can beused as a remedy of allergic disorders which is effective for thetreatment and prophylaxis of bronchial asthma, eczema, urticaria,allergic gastrointestinal disorders, allergic rhinitis, or allergicconjunctivitis.

Thus, the present compound represented by the formula (I) and apharmacologically acceptable salt thereof can provide an anti-allergicagent and a remedy against asthma useful for humans and animals. Asexamples of the target diseases, there are mentioned bronchial asthma,eczema, urticaria, allergic gastrointestinal disorders, allergicrhinitis, allergic conjunctivitis, and the like. The compound of thepresent invention is effective for the therapy and prophylaxis of theseallergic disorders.

The compound represented by the formula (I) of the present invention anda pharmacologically acceptable salt thereof can be administered eitherorally or parenterally including inhalationally, intranasally,intraocularly, subcutaneously, intravenously, intramuscularly,intrarectally and percutaneously, preferably orally, and areadministered to human and other animals in a variety of dosage forms asa pharmaceutical suitable for oral or parenteral administration.

For instance, the compound of the present invention can be prepared inany one of the preparation forms including oral dosage forms such as atablet, a capsule, a granule, powder, a pill, a fine granule, a troche,a syrup and an emulsion, liquid agents for external application such asan inhalation agent, a nasal drop and a eye drop, injection agents suchas an intravenous injection and an intramuscular injection, anintrarectal agent such as a fatty suppository or an aqueous suppositoryand paints such as an ointment.

These preparations can be prepared in the conventional method with theconventionally used additives such as an excipient, a filler, a binder,a wetting agent, a disintegrant, a surface active agent, a lubricant, adispersing agent, a buffer, a preservative, a stabilizer, an antiseptic,a flavoring agent, an analgesic and a stabilizing agent. The non-toxicadditives which may be incorporated include for example lactose,fructose, glucose, starch, gelatin, magnesium carbonate, syntheticmagnesium silicate, talc, magnesium stearate, methylcellulose,carboxymethylcellulose or a salt thereof, gum arabic, olive oil,propylene glycol, polyethylene glycol, a syrup, vaseline, glycerol,ethanol, citric acid, sodium chloride, sodium sulfite, sodium phosphate,and the like.

The content of the present compound in a pharmaceutical depends on itsdosage form and is generally in a concentration of 1-70% by weight,preferably 5-50% by weight per total composition. The specific examplesof the method for preparing the preparation are illustrated inpreparation examples below. While the dose for the therapy andprophylaxis of allergic diseases is determined in consideration ofapplications, the age, sex and symptoms of a patient, it is generally inthe range of about 0.1-2,000 mg, preferably 5-400 mg per day for anadult, which can be administered in one or several times per day.

EXAMPLE

The present invention is described in detail with reference to examples,test examples and preparation examples, which are non-limiting and onlyfor illustration, so that a variety of variations and modifications maybe apparently made without departing from the scope of the presentinvention.

NMR data in the following examples are those measured with a 400 MHz NMRspectrometer and expressed by the δ values (ppm) on the basis of TMS.

Example 1

4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c! 1!benzazepine

(a) To a solution of diisopropylamine (6.6 ml, 47.1 mmole) intetrahydrofuran (80 ml) at -78° C. under an argon atmosphere was added2.5N butyllithium (17.4 ml, 43.5 mmole), and the mixture was stirred for30 minutes. To this reaction mixture were next added a solution of ethylpropionate (4.0 ml, 39.5 mmole) in tetrahydrofuran (20 ml) and asolution of 2-nitrobenzaldehyde (4.0 g, 26.5 mmole) in tetrahydrofuran(20 ml) in this sequence, and the resulting mixture was further stirredat -78° C. for 30 minutes. To the reaction mixture were addedtetrahydrofuran (10 ml) followed by water, and the mixture was extractedwith ethyl acetate. The organic layer was washed with dilutehydrochloric acid, a saturated aqueous sodium hydrogen carbonatesolution and a saturated aqueous saline in this sequence. After theorganic layer was dried over anhydrous magnesium sulfate, the solventwas removed under reduced pressure to give ethyl4-hydroxy-4-(2-nitrophenyl)-2-butynoate as an oily product. After theethyl 4-hydroxy-4-(2-nitrophenyl)-2-butynoate thus obtained wasdissolved in toluene (80 ml), 4-methoxybenzylazide (13.0 g, 79.7 mmole)was added to the solution and stirred under heating at 100° C. for 3hours. The reaction mixture was then cooled to room temperature.Precipitates were collected by filtration, washed with toluene anddesiccated to give ethyl 5-hydroxy-(2-nitrophenyl)methyl!-1-(4-methoxybenzyl)-1,2,3-triazole-4-carboxylate(a-2: highly polar product (MP)) (2.55 g, 15.7%). Furthermore, thefiltrate was concentrated and purified by silica gel columnchromatography (toluene:ethyl acetate=1:1) to give a 3:1 mixture (6.09g, 37.4%) of ethyl4-(hydroxy-(2-nitrophenyl)methyl)-1-(4-methoxybenzyl)-1,2,3-triazole-5-carboxylate(a-1: low polar product (LP)) and a compound a-2.

a-1 (LP): ¹ H-NMR (CDCl₃): δ1.25 (3H, t), 3.77 (3H, s), 4.11 (2H, q),5.78 (1H, d), 5.81 (1H, d), 6.83 (2H, d), 6.88 (1H, s), 7.21 (2H, d),7.45-7.50 (1H, m), 7.65-7.70 (1H, m), 7.94 (1H, d), 8.00-8.04 (1H, m).

EIMS: m/z 412 (M⁺).

a-2 (MP):

¹ H-NMR (CDCl₃): δ1.36-1.41 (3H, m ), 3.68 (3H, s), 4.35-4.45 (2H, m),5.48 (1H, d), 5.51 (1H, d), 5.71 (1H, d), 6.44 (1H, d), 6.61 (2H, d),6.95 (1H, d), 7.08 (2H, d), 7.20 (1H, ddd), 7.35 (1H, dd), 7.83 (1H,dd).

EIMS: m/z 412 (M⁺).

(b) To a solution of oxalyl chloride (2.7 ml, 31.0 mmole) at -78° C.under an argon atmosphere were added a solution of dimethylsulfoxide(4.3 ml, 60.6 mmole) in methylene chloride (18 ml) and a solution of the3:1 mixture (6.09 g, 14.8 mmole) of the compounds a-1 and a-2 obtainedin the preceding step (a) in methylene chloride (18 ml) in thissequence, and the mixture was stirred for 30 minutes. Triethylamine(21.5 ml, 153 mmole) was then added to the reaction mixture, which wasfurther stirred at room temperature for 1 hour. After a saturatedaqueous ammonium chloride solution was added, the reaction mixture wasextracted with ethyl acetate. The organic layer was washed with waterand saturated aqueous saline in this sequence and dried over theanhydrous magnesium sulfate, and the solvent was removed under reducedpressure. The residue was purified on a silica gel column bychromatography with toluene:ethyl acetate=9:1-2:1 to give ethyl1-(4-methoxybenzyl)-4-(2-nitrobenzoyl)-1,2,3-triazole-5-carboxylate(b-1: LP) (3.95 g, 65.0%) as a brown oily product, followed by ethyl1-(4-methoxybenzyl)-5-(2-nitrobenzoyl)-1,2,3-triazole-4-carboxylate(b-2: MP) (1.40 g, 23.0%) as a colorless powdery product.

b-1 (LP):

¹ H-NMR (CDCl₃): δ1.37 (3H, t), 3.79 (3H, s), 4.42 (2H, q), 5.72 (2H,s), 6.86 (2H, d), 7.25 (2H, d), 7.61 (1H, dd), 7.69 (1H, ddd), 7.78 (1H,ddd), 8.19 (1H, dd).

EIMS: m/z 410 (M⁺).

b-2 (MP):

¹ H-NMR (CDCl₃): δ1.13 (3H, t), 3.78 (3H, s), 4.05 (2H, q), 5.82 (2H,s), 6.86 (2H, d), 7.32 (1H, d), 7.38 (2H, d), 7.66-7.72 (2H, m),8.03-8.07 (1H, m).

(c) A 1N aqueous sodium hydroxide solution (50 ml) was added to asolution of1-(4-methoxybenzyl)-4-(2-nitrobenzoyl)-1,2,3-triazole-5-carboxylate(b-1) (10.17 g, 24.8 mmole) in tetrahydrofuran (100 ml), which wasstirred at room temperature for 2 hours. The aqueous layer was acidifiedwith hydrochloric acid, extracted with ethyl acetate and washed withsaturated aqueous saline. The organic layer was dried over anhydrousmagnesium sulfate, and the solvent was removed under reduced pressure togive 1-(4-methoxybenzyl)-4-(2-nitrobenzoyl)-1,2,3-triazole-5-carboxylicacid (c-1': LP) as a colorless crystalline powder. The product wasdissolved in methanol (80 ml), 10% palladium on carbon (800 mg) wasadded, and the mixture was stirred in the hydrogen atmosphere at roomtemperature for 10 hours. The reaction mixture was filtered throughcelite, and the filtrate was concentrated under reduced pressure.Precipitates were collected by filtration to give4-(2-aminobenzoyl)-1-(4-methoxybenzyl)-1,2,3-triazole-5-carboxylic acid(c-1: LP) (6.62 g, 75.8% over two steps) as a yellow crystalline powder.

c-1 (LP):

¹ H-NMR (CDCl₃): δ3.78 (3H, s), 6.04 (2H, s), 6.7-6.8 (1H, m), 6.86 (2H,d), 7.45 (2H, d).

Also, ethyl1-(4-methoxybenzyl)-5-(2-nitrobenzoyl)-1,2,3-triazole-4-carboxylate(b-2) (6.90 g, 16.8 mmole) obtained in the preceding step (b) washydrolyzed with 1N sodium hydroxide (35 ml) in tetrahydrofuran (100 ml)at room temperature in the same manner as described above to give1-(4-methoxybenzyl)-5-(2-nitrobenzoyl)-1,2,3-triazole-4-carboxylic acid(c-2': MP) as a colorless crystalline powder. The product was thendissolved in methanol (200 ml) and reduced under the atmosphere ofhydrogen in the presence of 10% palladium on carbon (607 mg) at roomtemperature for 1.5 hours to give5-(2-aminobenzoyl)-1-(4-methoxybenzyl)-1,2,3-triazole-4-carboxylic acid(c-2: MP) (5.51 g, 93.0%) as a yellow crystalline powder.

c-2' (MP):

¹ H-NMR (CDCl₃): δ3.78 (3H, s), 5.80 (2H, s), 6.87 (2H, d), 7.39-7.43(1H, m), 7.41 (2H, d), 7.63-7.71 (2H, m), 8.03 (1H, dd).

c-2 (MP):

¹ H-NMR (CD₃ OD): δ3.62 (3H, s), 5.42 (2H, s), 6.26-6.30 (1H, m),6.6-6.7 (1H, m), 6.65 (2H, d), 6.75 (1H, d), 7.03 (2H, d), 7.16-7.21(1H, m).

EIMS: m/z 352 (M⁺).

(d) To a solution of4-(2-aminobenzoyl)-1-(4-methoxybenzyl)-1,2,3-triazole-5-carboxylic acid(c-1) (6.62 g, 18.8 mmole) in methylene chloride (120 ml) were addedunder an argon atmosphere and ice cooling tributyamine (4.7 ml, 19.7mmole), 2-fluoro-1-methylpyridinium p-toluenesulfonate (5.85 g, 20.7mmole) and 3,4-dihydro-2H-pyrido 1,2-a!pyrimidin-2-one (3.34 g, 22.5mmole), and the mixture was stirred for 1 hour. Chloroform and waterwere added to the reaction mixture, which was extracted with chloroform.The chloroform layer was washed with dilute hydrochloric acid, asaturated aqueous sodium hydrogen carbonate solution, and saturatedaqueous saline in this sequence. The organic layer was dried withanhydrous magnesium sulfate, and the solvent was removed under reducedpressure. Crystallized solids were collected by filtration and washedwith diethyl ether to give3-(4-methoxybenzyl)-4(5H),10-dioxo-3H-1,2,3-triazolo 5.4-c!1!benzazepine (d-1: LP) (2.96 g, 47.1%) as a yellow crystalline powder.

d-1 (LP):

¹ H-NMR (DMSO-d₆): δ3.72 (3H, s), 6.08 (2H, s), 6.90 (2H, d), 7.31 (2H,d), 7.34 (1H, dd), 7.53 (1H, d), 7.70 (1H, ddd), 8.23 (1H, dd).

FDMS: m/z 335 (M⁺ +1).

Also, in the same manner as above,1-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine (d-2: MP) (2.77 g, 98.3%) was obtained as a yellowcrystalline powdery product from the compound obtained in the precedingstep (c) and5-(2-aminobenzoyl)-1-(4-methoxybenzyl)-1,2,3-triazole-4-carboxylic acid(c-2) (2.97 g, 8.43 mmole).

d-2 (MP):

¹ H-NMR (DMSO-d₆): δ3.71 (3H, s), 6.91 (2H, s), 6.90 (2H, d), 7.27-7.33(1H, m), 7.29 (2H, d), 7.53 (1H, d), 7.69-7.74 (1H, m), 8.17 (1H, dd).

(e) Anisole (1.0 ml) and trifluoroacetic acid (4.0 ml) were added to3-(4-methoxybenzyl)-4(5H),10-dioxo-3H-1,2,3-triazolo 5,4-c!1!benzazepine (d-1) (84 mg, 0.251 mmole), and the mixture was stirred at70° C. for 1 hour. The reaction solvent was removed under reducedpressure, and the residue was dissolved in an aqueous sodium hydroxideand purified on DIAION HP-20 (water:acetone=1:9-3:7) to give the titlecompound a sodium salt of 4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine (58 mg, 97.8%) as a colorless powder.

¹ H-NMR (D₂ O): δ:7.17-7.23 (2H, m), 7.48-7.53 (1H, m), 8.20 (1H, d).

Also, in the same manner as described above,4(5H),10-dioxo-1-(4-methoxybenzyl)-1H-1,2,3-triazolo 4,5-c!1!benzazepine (d-2) (3.11 g, 9.30 mmole) was deprotected with anisole(25 ml) and trifluoroacetic acid (100 ml), and the product waspost-treated in the same manner as above. Purification on DIAION HP-20(water:acetone=1:9-3:7) gave the title compound (949 mg, 43.2%) as acolorless powder.

Example 2

3-(4-methoxybenzyl)-4(5H),10-dioxo-3H-1,2,3-triazolo 5,4-c!1!benzazepine

(a) Ethyl1-(4-methoxybenzyl)-4-(2-nitrobenzoyl)-1,2,3-triazole-5-carboxylate (629mg, 1.53 mmole) was dissolved in ethanol (6.0 ml), and 10% palladium oncarbon (58 mg) was added. After the mixture was stirred under a hydrogenatmosphere at room temperature for 16 hours, 10% palladium on carbon (60mg) was added, and the mixture was further stirred for 2 hours. Thereaction mixture was filtered through celite, and the solvent wasremoved under reduced pressure. Precipitate was collected by filtrationto give ethyl4-(2-aminobenzoyl)-1-(4-methoxybenzyl)-1,2,3-triazole-5-carboxylate (548mg, 94.2%) as a yellow crystalline powder.

¹ H-NMR (CDCl₃): δ1.06 (3H, t), 3.80 (3H, s), 4.17 (2H, q), 5.86 (2H,s), 6.54-6.59 (1H, m), 6.69 (1H, d), 6.88 (2H, d), 7.24-7.32 (1H, m),7.34-7.41 (1H, m), 7.36 (2H, d).

(b) To an ice-cooled solution of4-(2-aminobenzoyl)-1-(4-methoxybenzyl)-1,2,3-triazole-5-carboxylate (216mg, 0.568 mmole) in dimethylsulfoxide (3.0 ml) was added under the argonatmosphere 60% sodium hydride (26 mg, 0.650 mmole), and the mixture wasstirred at room temperature for 17 hours and then at 50° C. for 2 hours.Water was added to the reaction mixture, and the mixture was extractedwith ethyl acetate and washed with water and a saturated aqueous salinein this sequence. After the organic layer was dried over anhydrousmagnesium sulfate, the solvent was removed under reduced pressure. Theresidue was purified by silica gel column chromatography (toluene:ethylacetate=6:1-3:1) to give the title compound (37 mg, 19.5%) as a yellowcrystalline powdery product which was the same as the compound d-1obtained in Example 1 (d).

The compounds having a methyl group introduced in R² -R⁵ respectivelycan be also synthesized with 2-nitrobenzaldehyde as the startingmaterial in the same method as described in Example 1 or 2. Examples ofthe compounds synthesized by the same method as in Example 1 aredescribed as Examples 3-6.

Example 3

6-methyl-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c! 1!benzazepine

a-1: Ethyl4-(hydroxy-(3-methyl-2-nitrophenyl)methyl)-1-(4-methoxybenzyl)-1,2,3-triazole-5-carboxylate;

¹ H-NMR (CDCl₃): δ1.27 (3H, t), 2.34 (3H, s), 3.78 (3H, s), 4.35 (2H,q), 5.05 (2H, s), 6.84 (2H, d), 6.91 (1H, d), 7.25 (2H, d).

a-2: Ethyl5-(hydroxy-(3-methyl-2-nitrophenyl)methyl!-1-(4-methoxybenzyl)-1,2,3-triazole-4-carboxylate;

¹ H-NMR (CDCl₃): δ1.40 (3H, t), 2.35 (3H, s), 3.70 (3H, s), 4.41 (2H,q), 5.46 (1H, d), 5.57 (1H, d), 5.73 (1H, d), 6.15 (1H, d), 6.44 (1H,d), 6.65 (2H, d), 6.99 (1H, t), 7.11 (2H, d), 7.18 (1H, d).

EIMS: m/z 426 (M⁺).

b-1: Ethyl1-(4-methoxybenzyl)-4-(3-methyl-2-nitrobenzoyl)-1,2,3-triazole-5-carboxylate;

¹ H-NMR (CDCl₃): δ1.26 (3H, t), 2.47 (3H, s), 3.79 (3H, s), 4.33 (2H,q), 5.76 (2H, s), 6.87 (2H, d), 7.28 (2H, d), 7.51 (1H, d), 7.52 (1H,d), 7.69 (1H, dd).

EIMS: m/z 424 (M⁺).

b-2: Ethyl1-(4-methoxybenzyl)-5-(3-methyl-2-nitrobenzoyl)-1,2,3-triazole-4-carboxylate;

¹ H-NMR (CDCl₃): δ1.05 (3H, t), 2.39 (3H, s), 3.70 (3H, s), 4.14 (2H,q), 5.62 (2H, s), 6.71 (2H, d), 6.80 (1H, dd), 7.16 (2H, d), 7.24 (1H,dd), 7.48 (1H, dd).

SIMS: m/z 425 (M⁺ +1).

c-1':1-(4-methoxybenzyl)-4-(3-methyl-2-nitrobenzoyl)-1,2,3-triazole-5-carboxylicacid;

¹ H-NMR (CDCl₃): δ2.61 (3H, s), 3.78 (3H, s), 6.04 (2H, s), 6.85 (2H,d), 7.42 (2H, d), 7.60-7.64 (3H, m).

SIMS: m/z 397 (M⁺ +1).

c-1:4-(2-amino-3-methylbenzoyl)-1-(4-methoxybenzyl)-1,2,3-triazole-5-carboxylicacid;

¹ H-NMR (CDCl₃): δ2.22 (3H, s), 3.78 (3H, s), 6.04 (2H, s), 6.68 (1H,dd), 6.86 (2H, d), 7.33 (1H, d), 7.45 (2H, d), 8.47 (1H, d).

SIMS: m/z 367 (M⁺ +1).

c-2 ':1-(4-methoxybenzyl)-5-(3-methyl-2-nitrobenzoyl)-1,2,3-triazole-4-carboxylicacid;

¹ H-NMR (CDCl₃): δ2.40 (3H, s), 3.72 (3H, s), 5.63 (2H, s), 6.75 (2H,d), 6.91 (1H, d), 7.21 (2H, d), 7.30 (1H, dd), 7.50 (1H, d).

SIMS: m/z 397 (M⁺ +1).

c-2:5-(2-amino-3-methylbenzoyl)-1-(4-methoxybenzyl)-1,2,3-triazole-4-carboxylicacid;

¹ H-NMR (CDCl₃): δ6.66 (2H, d), 7.06 (2H, d).

SIMS: m/z 366 (M⁺).

d-1: 3-(4-methoxybenzyl)-6-methyl-4(5H),10-dioxo-3H-1,2,3-triazolo5,4-c! 1!benzazepine;

¹ H-NMR (DMSO-d₆): δ2.5 (3H, s), 3.72 (3H, s), 6.00 (2H, s), 6.92 (2H,d), 7.29 (1H, dd), 7.35 (2H, d), 7.60 (1H, d), 7.90 (1H, d), 9.97 (1H,s).

EIMS: m/z 348 (M⁺).

d-2: 1-(4-methoxybenzyl)-6-methyl-4(5H),10-dioxo-3H-1,2,3-triazolo4,5-c! 1!benzazepine;

¹ H-NMR (DMSO-d₆): δ2.5 (3H, s), 3.71 (3H, s), 5.89 (2H, s), 6.90 (2H,d), 7.25 (1H, dd), 7.29 (2H, d), 7.62 (1H, d), 7.85 (1H, d), 9.65 (1H,s).

EIMS: m/z 348 (M⁺).

Title compound: Sodium salt of 6-methyl-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine;

¹ H-NMR (DMSO-d₆): δ2.5 (3H, s), 7.14 (1H, dd), 7.49 (1H, d), 7.98 (1H,d), 8.74 (1H, s).

Example 4

7-methyl-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c! 1!benzazepine

1:1 mixture of a-1: ethyl4-(hydroxy-(4-methyl-2-nitrophenyl)methyl)-1-(4-methoxybenzyl)-1,2,3-triazole-5-carboxylateand a-2: ethyl5-(hydroxy-(4-methyl-2-nitrophenyl)methyl!-1-(4-methoxybenzyl)-1,2,3-triazole-4-carboxylate;

¹ H-NMR (CDCl₃): δ1.34 (3/2H, t), 1.39 (3/2H, t), 2.35 (3/2H, s), 2.45(3/2H, s), 3.69 (3/2H, s), 3.78 (3/2H, s), 4.35-4.44 (2H, m), 5.41(1/2H, d), 5.50 (1/2H, d), 5.51 (1H, s), 5.68 (1/2H, d), 5.80 (1/2H, d),5.83 (1/2H, d), 6.33 (1/2H, d), 6.63 (1H, d), 6.84 (1H, d), 6.85-6.93(1H, m), 7.00 (1/2H, d), 7.07 (1H, d), 7.22 (1H, d), 7.49 (1/2H, d),7.64 (1/2H, s), 7.79 (1/2H, d), 7.86 (1/2H, s).

EIMS: m/z 426 (M⁺).

b-1: Ethyl1-(4-methoxybenzyl)-4-(4-methyl-2-nitrobenzoyl)-1,2,3-triazole-5-carboxylate;

¹ H-NMR (CDCl₃): δ1.36 (3H, t), 2.53 (3H, s), 3.79 (3H, s), 4.41 (2H,q), 5.72 (2H, s), 6.85 (2H, d), 7.24 (2H, d), 7.52 (1H, d), 7.56 (1H,dd), 7.97 (1H, d).

EIMS: m/z 424 (M⁺).

b-2: Ethyl1-(4-methoxybenzyl)-5-(4-methyl-2-nitrobenzoyl)-1,2,3-triazole-4-carboxylate;

¹ H-NMR (CDCl₃): δ1.14 (3H, t), 2.51 (3H, s), 3.77 (3H, s), 4.08 (2H,q), 5.77 (2H, s), 6.84 (2H, d), 7.20 (1H, d), 7.36 (2H, d), 7.45 (1H,dd), 7.80 (1H, d).

EIMS: m/z 424 (M⁺).

c-1':1-(4-methoxybenzyl)-4-(4-methyl-2-nitrobenzoyl)-1,2,3-triazole-5-carboxylicacid;

¹ H-NMR (CDCl₃): δ2.57 (3H, s), 3.77 (3H, s), 6.02 (2H, s), 6.84 (2H,d), 7.39 (2H, d), 7.49 (1H, d), 7.63 (1H, m), 8.08 (1H, s).

SIMS: m/z 397 (M⁺ +1).

c-1:4-(2-amino-4-methylbenzoyl)-1-(4-methoxybenzyl)-1,2,3-triazole-5-carboxylicacid;

¹ H-NMR (CDCl₃): δ2.32 (3H, s), 3.78 (3H, s), 6.04 (2H, s), 6.52 (1H,s), 6.57 (1H, d), 6.86 (2H, d), 7.45 (2H, d), 8.60 (1H, d).

SIMS: m/z 367 (M⁺ +1).

c-2':1-(4-methoxybenzyl)-5-(4-methyl-2-nitrobenzoyl)-1,2,3-triazole-4-carboxylicacid;

¹ H-NMR (CDCl₃): δ2.50 (3H, s), 3.79 (3H, s), 5.78 (2H, s), 6.88 (2H,d), 7.30 (1H, d), 7.42 (2H, d), 7.50 (1H, d), 7.84 (1H, s).

SIMS: m/z 396 (M⁺).

c-2:5-(2-amino-4-methylbenzoyl)-1-(4-methoxybenzyl)-1,2,3-triazole-4-carboxylicacid;

¹ H-NMR (CDCl₃): δ2.23 (3H, s), 3.69 (3H, s), 5.4-5.5 (2H, brs), 6.19(1H, d), 6.46 (1H, s), 6.57 (1H, d), 6.67 (2H, d), 7.07 (2H, d).

EIMS: m/z 366 (M⁺).

d-1: 3-(4-methoxybenzyl)-7-methyl-4(5H),10-dioxo-3H-1,2,3-triazolo5,4-c! 1!benzazepine;

¹ H-NMR (DMSO-d₆): δ2.36 (3H, s), 3.71 (3H, s), 6.07 (2H, s), 6.90 (2H,d), 7.17 (1H, d), 7.30 (1H, d), 7.31 (1H, d), 8.13 (1H, d), 11.44 (1H,s).

EIMS: m/z 348 (M⁺).

d-2: 1-(4-methoxybenzyl)-7-methyl-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine;

¹ H-NMR (DMSO-d₆): δ2.36 (3H, s), 3.71 (3H, s), 5.99 (2H, s), 6.90 (2H,d), 7.13 (1H, d), 7.28 (2H, d), 7.32 (1H, s), 8.07 (1H, d), 11.29 (1H,s).

EIMS: m/z 348 (M⁺).

Title compound: 7-methyl-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine;

¹ H-NMR (DMSO-d₆): δ2.37 (3H, s), 7.16 (1H, d), 7.36 (1H, s), 8.20 (1H,d), 11.2-11.4 (1H, brs).

FDMS: m/z 228 (M⁺).

Example 5

8-methyl-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c! 1!benzazepine

1:1 mixture of a-1: ethyl4-(hydroxy-(5-methyl-2-nitrophenyl)methyl)-1-(4-methoxybenzyl)-1,2,3-triazole-5-carboxylateand a-2: ethyl5-(hydroxy-(5-methyl-2-nitrophenyl)methyl!-1-(4-methoxybenzyl)-1,2,3-triazole-4-carboxylate;

¹ H-NMR (CDCl₃): δ1.35 (3/2H, t), 1.37 (3/2H, t), 2.06 (3/2H, s), 2.46(3/2H, s), 3.70 (3/2H, s), 3.78 (3/2H, s), 4.37 (1H, dq), 4.41 (1H, q),5.30 (1/2H, d), 5.52 (1/2H, d), 5.77 (1/2H, d), 5.78 (1/2H, d), 5.84(1/2H, d), 6.05 (1/2H, d), 6.58-8.02 (7H, m).

EIMS: m/z 426 (M⁺).

b-1: Ethyl1-(4-methoxybenzyl)-4-(5-methyl-2-nitrobenzoyl)-1,2,3-triazole-5-carboxylate;

¹ H-NMR (CDCl₃): δ1.37 (3H, t), 2.49 (3H, s), 3.78 (3H, s), 4.42 (2H,q), 5.72 (2H, s), 6.85 (2H, d), 7.24 (2H, d), 7.36 (1H, s), 7.45 (1H,dd), 8.09 (1H, d).

EIMS: m/z 424 (M⁺).

b-2: Ethyl1-(4-methoxybenzyl)-5-(5-methyl-2-nitrobenzoyl)-1,2,3-triazole-4-carboxylate;

¹ H-NMR (CDCl₃): δ1.14 (3H, t), 2.42 (3H, s), 3.78 (3H, s), 4.06 (2H,q), 5.82 (2H, s), 6.86 (2H, d), 6.98 (1H, s), 7.37 (2H, d), 7.44 (1H,dd), 7.96 (1H, d).

EIMS: m/z 424 (M⁺).

c-2':1-(4-methoxybenzyl)-5-(5-methyl-2-nitrobenzoyl)-1,2,3-triazole-4-carboxylicacid;

¹ H-NMR (CDCl₃): δ2.48 (3H, s), 3.80 (3H, s), 5.82 (2H, s), 6.89 (2H,d), 7.10 (1H, d), 7.43 (2H, d), 7.45 (1H, dd), 7.98 (1H, d).

SIMS: m/z 397 (M⁺ +1).

c-2:5-(2-amino-5-methylbenzoyl)-1-(4-methoxybenzyl)-1,2,3-triazole-4-carboxylicacid;

¹ H-NMR (DMSO-d₆): δ1.92 (3H, s), 3.67 (3H, s), 5.39 (2H, s), 6.35-7.70(7H, m), 13.25 (1H, brs).

EIMS: m/z 367 (M⁺ +1).

d-2: 1-(4-methoxybenzyl)-8-methyl-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine;

¹ H-NMR (DMSO-d₆): δ2.34 (3H, s), 3.72 (3H, s), 6.00 (2H, s), 6.90 (2H,d), 7.29 (2H, d), 7.43 (1H, d), 7.53 (1H, d), 7.96 (1H, s), 11.32 (1H,s).

EIMS: m/z 348 (M⁺).

Title compound: Sodium salt of 8-methyl-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine;

¹ H-NMR (DMSO-d₆): δ2.34 (3H, s), 7.39 (2H, s), 8.06 (1H, s), 10.58 (1H,s).

FDMS: m/z 228 (M⁺ -Na+1).

Example 6

9-methyl-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c! 1!benzazepine

a-1: Ethyl4-(hydroxy-(2-methyl-6-nitrophenyl)methyl)-1-(4-methoxybenzyl)-1,2,3-triazole-5-carboxylate;

¹ H-NMR (CDCl₃): δ1.29 (3H, t), 2.42 (3H, s), 3.79 (3H, s), 4.35 (2H,dq), 4.46 (1H, d), 5.82 (2H, s), 6.47 (1H, d), 6.85 (2H, d), 7.19 (2H,d), 7.35 (1H, dd), 7.43 (1H, d), 7.58 (1H, dd).

a-2: Ethyl5-(hydroxy-(2-methyl-6-nitrophenyl)methyl!-1-(4-methoxybenzyl)-1,2,3-triazole-4-carboxylate;

¹ H-NMR (CDCl₃): δ1.41 (3H, t), 1.91 (3H, s), 3.77 (3H, s), 4.42 (2H,q), 5.22 (1H, d), 5.57 (1H, d), 5.70 (1H, brd), 6.46 (1H, d), 6.71 (2H,d), 6.75 (2H, d), 7.22 (1H, d), 7.36 (1H, dd), 7.58 (1H, d).

EIMS: m/z 426 (M⁺).

b-1: Ethyl1-(4-methoxybenzyl)-4-(2-methyl-6-nitrobenzoyl)-1,2,3-triazole-5-carboxylate;

¹ H-NMR (CDCl₃): δ1.38 (3H, t), 2.32 (3H, s), 3.79 (3H, s), 4.44 (2H,q), 5.73 (2H, s), 6.86 (2H, d), 7.27 (2H, d), 7.52 (1H, dd), 7.61 (1H,dd), 8.10 (1H, dd).

EIMS: m/z 424 (M⁺).

b-2: Ethyl1-(4-methoxybenzyl)-5-(2-methyl-6-nitrobenzoyl)-1,2,3-triazole-4-carboxylate;

¹ H-NMR (CDCl₃): δ1.16 (3H, t), 2.04 (3H, s), 3.80 (3H, s), 4.00 (2H,dq), 5.97 (2H, d), 6.89 (2H, dt), 7.45 (2H, dt), 7.51 (1H, dd), 7.55(1H, dd), 7.04 (1H, dd).

SIMS: m/z 425 (M⁺ +1).

c-1':1-(4-methoxybenzyl)-4-(2-methyl-6-nitrobenzoyl)-1,2,3-triazole-5-carboxylicacid;

¹ H-NMR (CDCl₃): δ2.31 (3H, s), 3.79 (3H, s), 6.03 (2H, brs), 6.86 (2H,d), 7.43 (2H, d), 7.63 (1H, dd), 7.68 (1H, dd), 8.18 (1H, dd), 13.80(1H, brs).

SIMS: m/z 397 (M⁺ +1).

c-1:4-(2-amino-6-methylbenzoyl)-1-(4-methoxybenzyl)-1,2,3-triazole-5-carboxylicacid;

¹ H-NMR (DMSO-d₆): δ1.82 (3H, s), 3.74 (3H, s), 5.76 (2H, s), 6.37 (1H,d), 6.64 (1H, d), 6.93 (2H, d), 7.08 (1H, dd), 7.23 (2H, d).

SIMS: m/z 367 (M⁺ +1).

c-2':1-(4-methoxybenzyl)-5-(2-methyl-6-nitrobenzoyl)-1,2,3-triazole-4-carboxylicacid;

¹ H-NMR (DMSO-d₆): δ2.09 (3H, s), 3.81 (3H, s), 6.00 (2H, brd), 7.02(2H, d), 7.40 (2H, d), 7.75 (1H, dd), 7.81 (1H, d), 8.15 (1H, d), 13.70(1H, brs).

SIMS: m/z 397 (M⁺ +1).

c-2:5-(2-amino-6-methylbenzoyl)-1-(4-methoxybenzyl)-1,2,3-triazole-4-carboxylicacid;

¹ H-NMR (DMSO₆): δ1.48 (3H, s), 3.65 (3H, s), 5.30 (2H, brs), 6.20-7.45(7H, m).

SIMS: m/z 367 (M⁺ +1).

d-1: 3-(4-methoxybenzyl)-9-methyl-4(5H),10-dioxo-3H-1,2,3-triazolo5,4-c! 1!benzazepine;

¹ H-NMR (DMSO-d₆): δ2.49 (3H, s), 3.72 (3H, s), 5.98 (2H, s), 6.90 (2H,d), 7.19 (1H, d), 7.30-7.36 (1H, m), 7.32 (2H, d), 7.47 (1H, dd), 11.27(1H, s).

EIMS: m/z 348 (M⁺).

d-2: 1-(4-methoxybenzyl)-9-methyl-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine;

¹ H-NMR (DMSO-d₆): δ2.25 (3H, s), 3.72 (3H, s), 5.85 (2H, s), 6.91 (2H,d), 7.11 (1H, d), 7.23 (2H, d), 7.33 (1H, d), 7.47 (1H, dd), 11.07 (1H,s).

EIMS: m/z 348 (M⁺).

Title compound: Sodium salt of 9-methyl-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine;

¹ H-NMR (DMSO-d₆): δ2.47 (3H, s), 7.03 (1H, d), 7.25 (1H, d), 7.32 (1H,dd), 10.22 (1H, s).

FDMS: m/z 228 (M⁺ -Na+1).

The 1:1 mixture of the compounds a-1 and a-2 in Example 5 can also beconverted into the compounds b-1 and b-2 in Example 5 by the oxidationreaction in Example 7 below.

Example 7

Ethyl1-(4-methoxybenzyl)-4-(5-methyl-2-nitrobenzoyl)1,2,3-triazole-5-carboxylateand

Ethyl1-(4-methoxybenzyl)-5-(5-methyl-2-nitrobenzoyl)1,2,3-triazole-4-carboxylateand

To the solution of the 1:1 mixture (1.76 g, 4.13 mmole) of ethyl4-(hydroxy-(5-methyl-2-nitrophenyl)methyl)-1-(4-methoxybenzyl)-1,2,3-triazole-5-carboxylate(Example 5, a-1) and ethyl5-(hydroxy-(5-methyl-2-nitrophenyl)methyl!-1-(4-methoxybenzyl)-1,2,3-triazole-4-carboxylate(Example 5, a-2) in methylene chloride (40 ml) was added manganesedioxide (1.8 g, 20.7 mmole), and the mixture was stirred at roomtemperature for 2 hours. Manganese dioxide (total amount: 3.6 g, 41.4mmole) was further added gradually, and the mixture was stirred at roomtemperature for 7.5 hours to complete the reaction. The reaction mixturewas filtered through celite, and the filtrate was removed under reducedpressure to give a crude product (1.69 g). The product was purified bysilica gel column chromatography (ethyl acetate:hexane=1:3-1:2) to givethe same title compounds as the compounds b-1 and b-2 obtained in thestep (b) of Example 5, that is ethyl1-(4-methoxybenzyl)-4-(5-methyl-2-nitrobenzoyl)-1,2,3-triazole-5-carboxylate(772 mg, 44%) as a yellow oil and ethyl1-(4-methoxybenzyl)-5-(5-methyl-2-nitrobenzoyl)-1,2,3-triazole-4-carboxylate(764 mg, 44%) as a yellow powder.

Example 8

8-hydroxy-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c! 1!benzazepine

(a) The 1:1 mixture of ethyl4-(hydroxy-(5-(4-methoxybenzyloxy)-2-nitrophenyl)methyl)-1-(4-methoxybenzyl)-1,2,3-triazole-5-carboxylate(a-1) and ethyl5-(hydroxy-(5-(4-methoxybenzyloxy)-2-nitrophenyl)methyl!-1-(4-methoxybenzyl)-1,2,3-triazole-4-carboxylate(a-2) was obtained in the same manner as in Example 1, except that2-nitrobenzaldehyde was replaced by5-(4-methoxybenzyloxy)-2-nitrobenzaldehyde.

¹ H-NMR (CDCl₃): δ1.32-1.40 (3H, m), 3.63-3.85 (6H, m), 4.31-4.46 (2H,m), 5.05-6.07 (5H, m), 6.57-8.20 (11H, m).

EIMS: m/z 548 (M⁺).

(b) The 1:1 mixture of ethyl1-(4-methoxybenzyl)-4-(5-(4-methoxybenzyloxy)-2-nitrobenzoyl)-1,2,3-triazole-5-carboxylate(b-1) and ethyl1-(4-methoxybenzyl)-5-(5-(4-methoxybenzyloxy)-2-nitrobenzoyl!-1,2,3-triazole-4-carboxylate(b-1) was obtained by oxidizing the 1:1 mixture of the compounds a-1 anda-2 obtained in the preceding step (a) in the same manner as in Example7.

¹ H-NMR (CDCl₃): δ1.16 (3/2H, t), 1.37 (3/2H, t), 3.76 (3/2H, s), 3.79(3/2H, s), 3.82 (3/2H, s), 3.83 (3/2H, s), 4.06 (1H, q), 4.42 (1H, q),5.00 (1H, s), 5.08 (1H, s), 5.72 (1H, s), 5.84 (1H, s), 6.71-7.45 (10H,m), 8.08 (1/2H, d), 8.19 (1/2H, d).

The title compound was obtained by subjecting the compounds obtained instep (b) as a mixture to alkaline hydrolysis in the same manner as inthe steps (c) and (d) of Example 1, followed by reduction, cyclizationand deprotection.

1:1 mixture of

c-1':1-(4-methoxybenzyl)-4-(5-(4-methoxybenzyloxy)-2-nitrobenzoyl)-1,2,3-triazole-5-carboxylicacid, and

c-2':1-(4-methoxybenzyl)-5-(5-(4-methoxybenzyloxy)-2-nitrobenzoyl!-1,2,3-triazole-4-carboxylicacid;

¹ H-NMR (CDCl₃): δ3.78 (3H, s), 3.83 (3H, s), 5.04 (1H, s), 5.10 (1H,s), 5.85 (1H, s), 6.02 (1H, s), 6.82-7.05 (5H, m), 7.13 (1/2H, dd), 7.21(1/2H, dd), 7.29-7.38 (2H, m), 7.38-7.48 (2H, m), 8.11 (1/2H, d), 8.27(1/2H, d).

1:1 mixture of

c-1:4-(2-amino-5-(4-methoxybenzyloxy)benzoyl)-1-(4-methoxybenzyl)-1,2,3-triazole-5-carboxylicacid, and

c-2:5-(2-amino-5-(4-methoxybenzyloxy)benzoyl)-1-(4-methoxybenzyl)-1,2,3-triazole-4-carboxylicacid;

¹ H-NMR (DMSO-d₆): δ3.63-3.80 (6H, m), 4.52-5.05 (2H, m), 5.55-6.05 (2H,m), 6.39-7.71 (11H, m).

1:1 mixture of

d-1:3-(4-methoxybenzyl)-8-(4-methoxybenzyloxy)-4(5H),10-dioxo-3H-1,2,3-triazolo5,4-c! 1!benzazepine, and

d-2:1-(4-methoxybenzyl)-8-(4-methoxybenzyloxy)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine;

¹ H-NMR (DMSO-d₆): δ3.72 (3H, s), 3.76 (3H, s), 5.09 (1H, s), 5.11 (1H,s), 6.01 (1H, s), 6.09 (1H, s), 6.90 (1H, d), 6.94 (1H, d), 7.26-7.35(2H, m), 7.37-7.46 (3H, m), 7.49 (1/2H, d), 7.50 (1/2H, d), 7.68 (1/2H,d), 7.75 (1/2H, d), 11.32 (1/2H, s), 11.46 (1/2H, s).

EIMS: m/z 470 (M⁺).

Title compound: 8-hydroxy-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine;

¹ H-NMR (DMSO-d₆): δ7.19 (1H, dd), 7.45 (1H, d), 7.66 (1H, d), 9.89 (1H,brs), 11.29 (1H, brs).

SIMS: m/z 231 (M⁺ +1).

The compounds wherein a methyl group was introduced into R¹ wassynthesized in the method described in Example 9 or 10.

Example 9

5-methyl-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c! 1!benzazepine (a) Underthe argon atmosphere, 60% sodium hydride (14 mg, 0.350 mmole) was addedto a solution of 3-(4-methoxybenzyl)-4(5H),10-dioxo-3H-1,2,3-triazolo5,4-c! 1!benzazepine (100 mg, 0.299 mmole) in dimethylformamide (3.0 ml)under ice-cooling, and the mixture was stirred for 1.5 hours. A solutionof methyl iodide (57 mg, 0.402 mmole) in dimethylformamide (1.5 ml) wasadded, and the mixture was stirred at room temperature for 13 hours. Icewas added to the mixture, which was then extracted with ethyl acetate.The extract was washed with water and a saturated aqueous saline in thissequence. After the organic layer was dried over anhydrous magnesiumsulfate, the solvent was removed under reduced pressure. The residue waspurified by silica gel column chromatography (toluene: ethylacetate=5:1) to give3-(4-methoxybenzyl)-5-methyl-4(5H),10-dioxo-3H-1,2,3-triazolo 5,4-c!1!benzazepine (95 mg, 91.2%) as a yellow crystalline powder.

¹ H-NMR (CDCl₃): δ3.62 (3H, s), 3.75 (3H, s), 6.03 (2H, s), 6.83 (2H,d), 7.32-7.40 (2H, m), 7.38 (2H, d), 7.57-7.63 (1H, m), 7.99 (1H, dd).

FDMS: m/z 348 (M⁺).

(b) Anisole (1.0 ml) and trifluoroacetic acid (4.0 ml) were added to the3-(4-methoxybenzyl)-5-methyl-4(5H),10-dioxo-3H-1,2,3-triazolo 5,4-c!1!benzazepine (82 mg, 0.235 mmole) obtained in the preceding step (a),and the mixture was stirred at 70° C. for 1 hour. The solvent wasremoved under reduced pressure, and precipitates were collected byfiltration and washed with diethyl ether to give the title compound (44mg, 82.0%) as a red crystalline powder.

¹ H-NMR (DMSO-d₆): δ2.94 (3H, s), 6.49-6.54 (total 1H, m), 6.83 (1H, d),7.10-7.25 (1H, m), 7.44-7.50 (1H, m), 8.72 (1H, brs).

Example 10

3-(4-methoxybenzyl)-5-methyl-4(5H),10-dioxo-3H-1,2,3-triazolo 5,4-c!1!benzazepine

(a) Under the argon atmosphere, potassium carbonate (855 mg, 6.19 mmole)and benzyl chloroformate (0.70 ml, 4.90 mmole) were added underice-cooling to a solution of ethyl4(2-aminobenzoyl)-1-(4-methoxybenzyl)-1,2,3-triazole-5-carboxylate (1.51g, 3.97 mmole) in tetrahydrofuran (30 ml), and the mixture was stirredunder ice-cooling for 1 hour. After stirring at room temperature forfurther 19 hours, potassium carbonate (2.0 g, 14.47 mmole) and benzylchloroformate (1.5 ml, 10.51 mmole) were additionally added to thereaction mixture, which was further stirred at 50° C. for 6 hours. Afterwater was added to the reaction mixture, it was extracted with ethylacetate and washed with water and a saturated aqueous saline in thissequence. The organic layer was dried over anhydrous magnesium sulfate,the solvent was removed under reduced pressure. The residue wascollected by filtration and washed with diethyl ether to give ethyl4(2-(N-benzyloxycarbonyl)amino)benzoyl-1-(4-methoxybenzyl)-1,2,3-triazole-5-carboxylate(1.21 g, 59.2%) as a yellow crystalline powder.

¹ H-NMR (CDCl₃): δ1.03 (3H, t), 3.80 (3H, s), 4.16 (2H, q), 5.23 (2H,s), 5.84 (2H, s), 6.88 (2H, d), 6.99-7.04 (1H, m), 7.33-7.44 (7H, m),7.58 (1H, dd), 7.66 (1H, d), 8.52 (1H, d).

(b) Under the argon atmosphere, 60% sodium hydride (83 mg, 2.08 mmole)was added to a solution of4(2-(N-benzyloxycarbonyl)amino)benzoyl-1-(4-methoxybenzyl)-1,2,3-triazole-5-carboxylate(702 mg, 1.36 mmole) in dimethylformamide (14 ml) under ice-cooling, andthe mixture was stirred for 30 minutes. Methyl iodide (0.17 ml, 2.74mmole) was next added, and the mixture was stirred at room temperaturefor 30 minutes. Ice was added to the mixture, which was then extractedwith ethyl acetate and washed with water and a saturated aqueous salinein this sequence. After the organic layer was dried over anhydrousmagnesium sulfate, the solvent was removed under reduced pressure. Theresidue was purified by silica gel column chromatography (toluene: ethylacetate=6:1) to give4-(2-(N-benzyloxycarbonyl-N-methyl)amino)benzoyl-1-(4-methoxybenzyl)-1,2,3-triazole-5-carboxylate(646 mg, 89.9%) as a yellow crystalline powder.

¹ H-NMR (CDCl₃): δ1.10 (3H, t), 3.12 (3H, s), 3.78 (3H, s), 4.16 (2H,q), 4.7-5.2 (2H, brs), 5.75 (2H, s), 6.87 (2H, d), 7.1-7.4 (9H, m),7.53-7.57 (1H, m), 7.76-7.79 (1H, m).

EIMS: m/z 528 (M⁺).

(c) A 1N aqueous sodium hydroxide solution (2.4 ml) was added to asolution of4-(2-(N-benzyloxycarbonyl-N-methyl)aminobenzoyl)-1-(4-methoxybenzyl)-1,2,3-triazole-5-carboxylate(646 mg, 1.22 mmole) in tetrahydrofuran (7.0 ml), and the mixture wasstirred at room temperature for 12 hours. The reaction mixture waswashed with diethyl ether. The aqueous layer acidified with hydrochloricacid was extracted with ethyl acetate, and the ethyl acetate extract waswashed with water and a saturated aqueous saline in this sequence. Theorganic layer was dried over anhydrous magnesium sulfate, and thesolvent was removed under reduced pressure. The residue was collected byfiltration, pulverized with diethyl ether to give4(2-(N-methyl)amino)benzoyl-1-(4-methoxybenzyl)-1,2,3-triazole-5-carboxylicacid (303 mg, 67.8%).

¹ H-NMR (CDCl₃): δ3.78 (3H, s), 6.03 (2H, s), 6.67-6.73 (1H, m), 6.79(1H, d), 6.86 (2H, d), 7.44 (2H, d), 7.48-7.53 (1H, m), 8.71 (1H, d),8.81 (1H, brs).

EIMS: m/z 366 (M⁺).

(d) Under the argon atmosphere, tributylamine (0.096 ml, 0.403 mmole),2-fluoro-1-methylpyridinium p-toluenesulfonate (122 mg, 0.431 mmole) and3,4-dihydro-2H-pyrido 1,2-a!pyrimidin-2-one (71 mg, 0.479 mmole) wereadded to a solution of4-(2-(N-methyl)amino)benzoyl-1-(4-methoxybenzyl)-1,2,3-triazole-5-carboxylicacid (141 mg, 0.385 mmole) in methylene chloride (3.0 ml) in an icebath, and the mixture was stirred for 1 hour. The reaction mixture wasdiluted with chloroform and washed with dilute hydrochloric acid, asaturated aqueous sodium hydrogen carbonate solution and a saturatedaqueous saline in this sequence. The organic layer was dried overanhydrous magnesium sulfate, and the solvent was removed under reducedpressure. The residue was purified by silica gel column chromatography(toluene:ethyl acetate=9:1-4:1) to give the title compound,3-(4-methoxybenzyl)-5-methyl-4(5H),10-dioxo-3H-1,2,3-triazolo 5,4-c!1!benzazepine (55 mg, 41.0%), as a yellow crystalline product which wasthe same as the compound obtained in Example 9 (a).

Example 11

7-formyl-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c! 1!benzazepine

(a) Under the argon atmosphere, 1.56N butyllithium (19.6 ml, 30.6 mmole)was added to a solution of diisopropylamine (4.7 ml, 33.6 mmole) intetrahydrofuran (80 ml) at -78° C., and the mixture was stirred for 30minutes. Next, a solution of ethyl propiolate (2.8 ml, 27.6 mmole) intetrahydrofuran (20 ml) and a solution of4-dimethoxymethyl-2-nitrobenzaldehyde (4.2 g, 18.5 mmole) intetrahydrofuran (20 ml) were added to the reaction mixture in thissequence, and the mixture was stirred at -78° C. for additional 30minutes. After acetic acid (3.5 ml, 61.1 mmole) and water weresequentially added to the reaction mixture, which was then extractedwith ethyl acetate. The organic layer was washed with dilutehydrochloric acid, a saturated aqueous sodium hydrogen carbonatesolution and a saturated aqueous saline in this sequence.

The organic layer was dried over anhydrous magnesium sulfate, and thesolvent was removed under reduced pressure to give ethyl4-hydroxy-4(4-dimethoxymethyl-2-nitrophenyl)-2-butynoate as an oil. To asolution of the product thus obtained in toluene (80 ml) was added4-methoxybenzylazide (9.1 g, 55.5 mmole), and the reaction mixture wasstirred under heating at 100° C. for 15 hours. After the reactionmixture was cooled to room temperature, the solvent was removed underreduced pressure, and the residue was purified by silica gel columnchromatography (hexane:ethyl acetate=2:1-1:1) to give a 1:1 mixture ofethyl4-(hydroxy-(4-dimethoxymethyl-2-nitrophenyl)methyl)-1-(4-methoxybenzyl)-1,2,3-triazole-5-carboxylate(a-1: low polar product (LP)) and ethyl5-(hydroxy-(4-dimethoxymethyl-2-nitrophenyl)methyl)-1-(4-methoxybenzyl)-1,2,3-triazole-4-carboxylate(a-2: highly polar product (MP)) (8.62 g, 95.7%).

¹ H-NMR (CDCl₃): δ1.34 (3/2H, t), 1.39 (3/2H, t), 3.287 (3/2H, s), 3.293(3/2H, s), 3.34 (3/2H, s), 3.35 (3/2H, s), 3.67 (3/2H, s), 3.78 (3/2H,s), 3.67-4.43 (2H, m), 5.34 (1/2H, s), 5.48 (1/2H, s), 5.51 (1H, s),5.52 (1/2H, d), 5.72 (1/2H, d), 5.80 (1/2H, d), 5.83 (1/2H, d), 6.41(1/2H, d), 6.60 (1H, d), 6.83-6.95 (3/2H, m), 6.84 (1H, d), 7.07 (1H,d), 7.22 (1H, d), 7.75-7.78 (1/2H, m), 7.92 (1/2H, s), 7.92-7.78 (1/2H,m), 8.15 (1/2H, s).

EIMS: m/z 486 (M⁺).

(b) To a solution of the 1:1 mixture (13.1 g, 27.0 mmole) of thecompounds a-1 and a-2 obtained by the procedure of the preceding step(a) in methylene chloride (260 ml) was added manganese dioxide (53.0 g)in two portions, and the mixture was stirred at room temperature for 15hours. After the reaction mixture was filtered through celite and solidsretained on the celite was washed with methylene chloride, the solventwas removed under reduced pressure. The residue thus obtained waspurified by silica gel column chromatography (toluene:ethylacetate=9:1-1:1) to give ethyl1-(4-methoxybenzyl)-4-(4-dimethoxymethyl-2-nitrobenzoyl)-1,2,3-triazole-5-carboxylate(b-1: LP) (4.86 g, 37.2%) as a brown oil from the fraction eluted withtoluene:ethyl acetate=9:1, and ethyl1-(4-methoxybenzyl)-5-(4-dimethoxymethyl-2-nitrobenzoyl)-1,2,3-triazole-4-carboxylate(b-2: MP) (6.27 g, 48.0%) as a colorless crystalline powder from thefraction eluted with toluene:ethyl acetate=1:1.

b-1 (LP);

¹ H-NMR (CDCl₃): δ1.36 (3H, t), 3.36 (6H, s), 3.77 (3H, s), 4.41 (2H,q), 5.51 (1H, s), 5.71 (2H, s), 6.85 (2H, d), 7.24 (2H, d), 7.61 (1H,d), 7.85 (1H, d), 8.27 (1H, s).

SIMS: m/z 485 (M⁺ +1).

b-2 (MP);

¹ H-NMR (CDCl₃): δ1.14 (3H, s), 3.34 (6H, s), 3.77 (3H, s), 4.04 (2H,q), 5.50 (1H, s), 5.81 (2H, s), 6.85 (2H, d), 7.31 (1H, d), 7.37 (2H,d), 7.75 (1H, d), 8.15 (1H, s).

SIMS: m/z 485 (M⁺ +1). (c) To a solution of ethyl1-(4-methoxybenzyl)-4-(4-dimethoxymethyl-2-nitrobenzoyl)-1,2,3-triazole-5-carboxylate(b-1) (14.11 g, 29.1 mmole) obtained in the preceding step (b) intetrahydrofuran (120 ml) was added a 1N aqueous sodium hydroxidesolution (60 ml), and the mixture was stirred at room temperature for 2hours. After the aqueous layer was acidified with hydrochloric acid, itwas extracted with ethyl acetate and washed with a saturated aqueoussaline. The organic layer was dried over anhydrous magnesium sulfate,and the solvent was removed under reduced pressure to give1-(4-methoxybenzyl)-4-(4-dimethoxymethyl-2-nitrobenzoyl)-1,2,3-triazole-5-carboxylicacid (c-1': LP) as a colorless crystalline powder. The product was nextdissolved in a mixed solvent of ethanol (300 ml) and ethyl acetate (300ml), 10% palladium on carbon (1.17 g) was added, and the mixture wasstirred under the hydrogen atmosphere at room temperature for 3 hours.After the reaction mixture was filtered through celite, the filtrate wasconcentrated under reduced pressure, and the precipitates were collectedby filtration to give4-(2-amino-4-dimethoxymethylbenzoyl)-1-(4-methoxybenzyl)-1,2,3-triazole-5-carboxylicacid (c-1: LP) (9.82 g, 79.1%).

c-1' (LP);

¹ H-NMR (CDCl₃): δ3.39 (6H, s), 3.78 (3H, s), 5.55 (1H, s), 6.03 (2H,s), 6.85 (2H, d), 7.40 (2H, d), 7.59 (1H, d), 7.93 (1H, d), 8.39 (1H,s).

SIMS: m/z 457 (M⁺ +1).

c-1 (LP);

¹ H-NMR (CDCl₃): δ3.39 (6H, s), 3.78 (3H, s), 5.96 (2H, s), 6.88 (2H,d), 7.23 (1H, d), 7.41 (2H, d), 7.79 (1H, s), 8.17 (1H, d).

Similarly, ethyl1-(4-methoxybenzyl)-5-(4-dimethoxymethyl-2-nitrobenzoyl)-1,2,3-triazole-4-carboxylate(b-2) (1.49 g, 3.08 mmole) obtained in the preceding step (b) intetrahydrofuran (12 ml) was hydrolyzed with a 1N aqueous sodiumhydroxide solution (6 ml) at room temperature for 2 hours to give1-(4-methoxybenzyl)-5-(4-dimethoxymethyl-2-nitrobenzoyl)-1,2,3-triazole-4-carboxylicacid (c-2': MP) as a colorless crystalline powder.

The product was next dissolved in methanol (150 ml) and subjected tohydrogenation in the presence of 10% palladium on carbon (160 mg) underthe hydrogen atmosphere at room temperature for 3 hours to give5-(2-amino-4-dimethoxymethylbenzoyl)-1-(4-methoxybenzyl)-1,2,3-triazole-4-carboxylicacid (c-2: MP) as a yellow crystalline powder (1.10 g, 83.8%).

c-2' (MP);

¹ H-NMR (CDCl₃): δ3.34 (6H, s), 3.80 (3H, s), 5.52 (1H, s), 5.84 (2H,s), 6.90 (2H, d), 7.42 (2H, d), 7.44 (1H, d), 7.83 (1H, d), 8.21 (1H,s).

FDMS: m/z 456 (M⁺).

c-2 (MP);

¹ H-NMR (CDCl₃): δ3.29 (6H, s), 3.67 (3H, s), 5.3-5.5 (2H, m), 6.41 (1H,d), 6.65 (2H, d), 6.78 (1H, s), 7.05 (2H, d).

SIMS: m/z 427 (M⁺ +1).

(d) Under the argon atmosphere, tributylamine (0.115 ml, 0.483 mmole),2-fluoro-1-methylpyridinium p-toluenesulfonate (146 mg, 0.515 mmole) and3,4-dihydro-2H-pyrido 1,2-a!pyrimidin-2-one (85 mg, 0.574 mmole) wereadded under ice-cooling in this sequence to a solution of4(2-amino-4-dimethoxymethylbenzoyl)-1-(4-methoxybenzyl)-1,2,3-triazole-5-carboxylicacid (c-1) (98.6 mg, 0.231 mmole) in methylene chloride (2 ml), and themixture was stirred for 1 hour.

Chloroform and water were added to the reaction mixture, which wasextracted with chloroform. The organic layer was washed with dilutehydrochloric acid, a saturated aqueous sodium hydrogen carbonatesolution and a saturated aqueous saline. After the organic layer wasdried with anhydrous magnesium sulfate, the solvent was removed underreduced pressure. The residue thus obtained was purified by silica gelcolumn chromatography to give3-(4-methoxybenzyl)-7-dimethoxymethyl-4(5H),10-dioxo-3H-1,2,3-triazolo5,4-c! 1!benzazepine (d-1: LP) (34.4 mg, 36.5%).

d-1 (LP);

¹ H-NMR (CDCl₃): δ3.33 (6H, s), 3.72 (3H, s), 5.47 (1H, s), 6.07 (2H,s), 6.90 (2H, d), 7.30 (2H, d), 7.3-7.5 (1H, m), 7.61 (1H, s), 8.23 (1H,d), 11.51 (1H, brs).

SIMS: m/z 409 (M⁺ +1).

In the same way as described above, starting from5-(2-amino-4-dimethoxymethylbenzoyl)-1-(4-methoxybenzyl)-1,2,3-triazole-4-carboxylicacid (c-2) which was the compound obtained in the preceding step (c),1-(4-methoxybenzyl)-7-dimethoxymethyl-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine (d-2: MP) was obtained as a yellow crystallinepowder (1.21 g, 43.1%).

d-2 (MP);

¹ H-NMR (CDCl₃): δ3.27 (6H, s), 3.71 (3H, s), 5.46 (1H, s), 5.99 (2H,s), 6.90 (2H, d), 7.27-7.30 (3H, m), 7.61 (1H, s), 8.18 (1H, d), 11.36(1H, s).

(e) A 1N hydrochloric acid (10 ml) was added to a solution of3-(4-methoxybenzyl)-7-dimethoxymethyl-4(5H),10-dioxo-3H-1,2,3-triazolo5,4-c! 1!benzazepine (d-1) (311 mg, 0.760 mmole) in tetrahydrofuran (40ml), and the mixture was stirred at room temperature for 19 hours. Thereaction mixture was extracted with ethyl acetate, and the organic layerwas washed with a saturated aqueous sodium hydrogen carbonate solutionand a saturated aqueous saline in this sequence. After the organic layerwas dried over anhydrous magnesium sulfate, the solvent was removedunder reduced pressure. Precipitates were collected by filtration,pulverized with diethyl ether and desiccated to give7-formyl-3-(4-methoxybenzyl)-4(5H),10-dioxo-3H-1,2,3-triazolo 5,4-c!1!benzazepine (e-1: LP) as a yellow crystalline powder (253 mg, 91.9%).

e-1: (LP)

¹ H-NMR (DMSO-d₆): δ3.72 (3H, s), 6.08 (2H, s), 6.91 (2H, d), 7.32 (2H,d), 7.80 (1H, dd), 8.03 (1H, d), 8.39 (1H, d), 10.07 (1H, s), 11.73 (1H,s).

Similarly, starting from1-(4-methoxybenzyl)-7-dimethoxymethyl-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine (d-2) which is the compound obtained in thepreceding step (d), was obtained as a yellow crystalline powder (1.07 g,86.9%).

e-2: (MP)

¹ H-NMR (DMSO-d₆): δ3.72 (3H, s), 5.98 (2H, s), 6.91 (2H, d), 7.31 (2H,d), 7.74 (1H, d), 8.03 (1H, d), 8.32 (1H, d), 10.06 (1H, s), 11.60 (1H,s).

EIMS: m/z 362 (M⁺).

(f) Trifluoroacetic acid (1 ml) was added to 7-formyl1-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine (31.2 mg, 0.0861 mmole), and the mixture was stirred at60° C. for 1.5 hours. After the solvent was removed under reducedpressure, precipitates were collected by filtration, pulverized withethyl acetate and desiccated to give the title compound,7-formyl-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c! 1!benzazepine, as ayellow crystalline powder (11.2 mg, 53.7%).

¹ H-NMR (DMSO-d₆): δ7.77 (1H, dd), 8.07 (1H, s), 8.45 (1H, d), 10.07(1H, s), 11.65 (1H, s).

EIMS: m/z 242 (M⁺).

Example 12

7-ethyl-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c! 1!benzazepine

(a) Potassium tert-butoxide (473 mg, 4.22 mmole) was added to asuspension of methyltriphenylphosphonium bromide (1.64 g, 4.66 mmole) intetrahydrofuran (30 ml). After the reaction mixture was stirred at roomtemperature for 15 minutes, a solution of7-formyl-1-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine (303 mg, 0.836 mmole) in N,N-dimethylformamide (10 ml) wasadded, and the mixture was further stirred at room temperature for 30minutes. After the reaction was stopped with water, the mixture wasextracted with ethyl acetate, and the organic layer was washed with asaturated aqueous saline. The organic layer was dried over anhydrousmagnesium sulfate, and the solvent was removed under reduced pressure.Precipitates were collected by filtration, pulverized with diethyl etherand desiccated to give1-(4-methoxybenzyl)-4(5H),10-dioxo-7-vinyl-1H-1,2,3-triazolo 4,5-c!1!benzazepine (245 mg, 81.3%) as a yellow crystalline powder.

¹ H-NMR (DMSO-d₆): δ3.71 (3H, s), 5.54 (1H, d), 6.00 (2H, s), 6.02 (1H,d), 6.77 (1H, dd), 6.90 (2H, d), 7.29 (2H, d), 7.46 (1H, dd), 7.57 (1H,d), 8.15 (1H, d), 11.31 (1H, d).

EIMS: m/z 360 (M⁺).

(b) 1-(4-methoxybenzyl)-4(5H),10-dioxo-7-vinyl-1H-1,2,3-triazolo 4,5-c!1!benzazepine (1.60 g, 4.44 mmole) obtained in the preceding step (a)was dissolved in acetic acid (500 ml), 10% palladium on carbon (160 mg)was added, and the mixture was stirred under the hydrogen atmosphere atroom temperature for 13 hours. After the reaction mixture was filteredthrough celite, the solvent was removed under reduced pressure.Precipitates were collected by filtration, pulverized with diethyl etherand desiccated to give7-ethyl-1-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine as a yellow crystalline powder (1.44 g, 89.5%).

¹ H-NMR (DMSO-d₆): δ1.20 (3H, t), 2.66 (2H, q), 3.71 (3H, s), 6.00 (2H,s), 6.90 (2H, d), 7.17 (1H, d), 7.28 (2H, d), 7.38 (1H, s), 8.10 (1H,d), 11.27 (1H, s).

SIMS: m/z 363 (M⁺ +1).

(c) Anisole (40 ml) and trifluoroacetic acid (160 ml) were added to7-ethyl-1-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine (1.42 g, 3.92 mmole) obtained in the preceding step (forand the mixture was stirred at 70° C. for 2.5 hours. The solvent wasremoved under reduced pressure. Precipitates were collected byfiltration, pulverized with diethyl ether and desiccated to give thetitle compound, 7-ethyl-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine, as a yellow crystalline powder (927 mg, 97.6%).

¹ H-NMR (DMSO-d₆): δ1.21 (3H, t), 2.67 (2H, q), 7.20 (2H, d), 7.42 (1H,s), 8.22 (2H, s), 11.30 (1H, s).

SIMS: m/z 243 (M⁺ +1).

Example 13

4(5H),10-dioxo-7-vinyl-1H-1,2,3-triazolo 4,5-c! 1!benzazepine

Anisole (1.5 ml ) and trifluoroacetic acid (6 ml ) were added to1-(4-methoxybenzyl)-4(5H), 10-dioxo-7-vinyl-1H-1,2,3-triazolo 4, 5-c!1!benzazepine (120 mg, 0.332 mmole) obtained in Example 12 (a), and themixture was stirred at 60° C. for 2 hours. The solvent was removed underreduced pressure. Precipitates were collected by filtration, pulverizedwith diethyl ether and desiccated to give the title compound,4(5H),10-dioxo-7-vinyl-1H-1,2,3-triazolo 4,5-c! 1!benzazepine, as ayellow crystalline powder (81 mg, 100%).

¹ H-NMR (DMSO-d₆): δ5.54 (1H, d), 6.02 (1H, d), 6.78 (1H, dd), 7.49 (1H,d), 7.62 (1H, d), 8.28 (1H, d), 11.36 (1H, s).

SIMS: m/z 241 (M⁺ +1).

As will be illustrated in Examples 14 and 15, the compounds having apropyl group or an octyl group as a substituent at the 7-position weresynthesized in the same method described in Example 12.

Example 14

4(5H),10-dioxo-7-propyl-1H-1,2,3-triazolo 4,5-c! 1!benzazepine

Starting from7-formyl-1-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine (154 mg, 0.425 mmole), the following compounds wereprepared in the same procedures as described in Example 12, except thatmethyltriphenylphosphonium bromide was replaced byethyltriphenylphosphonium bromide.

(a) 1:1 mixture of1-(4-methoxybenzyl)-4(5H),10-dioxo-7-((E)-1-propenyl)-1H-1,2,3-triazolo4,5-c! 1!benzazepine and1-(4-methoxybenzyl)-4(5H),10-dioxo-7-((Z)-1-propenyl)-1H-1,2,3-triazolo4,5-c! 1!benzazepine (85 mg, 53.5%):

¹ H-NMR (DMSO-d₆): δ1.90-1.94 (3H, m), 3.71 (3H, s), 6.00 (2H, s),6.0-6.1 (1/2H, m), 6.4-6.6 (3/2H, m), 6.90 (2H, d), 7.23 (1/2H, d), 7.28(2H, d), 7.38 (1/2H, d), 7.45 (1/2H, s), 7.53 (1/2H, s), 8.11 (1/2H, d),8.15 (1/2H, d), 11.29 (1/2H, s), 11.37 (1/2H, d).

EIMS: m/z 374 (M⁺).

(b) 1-(4-methoxybenzyl)-4(5H),10-dioxo-7-propyl-1H-1,2,3-triazolo 4,5-c!1!benzazepine (83 mg, 96.7%):

¹ H-NMR (DMSO-d₆): δ0.90 (3H, t), 1.61 (2H, qq), 2.61 (2H, t), 3.71 (3H,s), 6.00 (2H, s), 6.90 (2H, d), 7.16 (1H, d), 7.28 (2H, d), 7.35 (1H,s), 8.10 (1H, d), 11.26 (1H, s).

EIMS: m/z 376 (M⁺).

(c) the title compound, 4(5H),10-dioxo-7-propyl-1H-1,2,3-triazolo 4,5-c!1!benzazepine (49 mg, 86.2%):

¹ H-NMR (DMSO-d₆): δ0.92 (3H, t), 1.63 (2H, qq), 2.62 (3H, t), 7.19 (1H,d), 7.39 (1H, s), 8.22 (1H, d), 11.30 (1H, s).

EIMS: m/z 256 (M⁺).

Example 15

7-octyl-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c! 1!benzazepine

Starting from7-formyl-1-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine (150 mg, 0.414 mmole), the following compounds wereprepared in the same procedures as described in Example 12, except thatmethyltriphenylphosphonium bromide was replaced byheptyltriphenylphosphonium bromide.

(a) 5:1 mixture of1-(4-methoxybenzyl)-7-((E)-1-octenyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine and1-(4-methoxybenzyl)-7-((Z)-1-octenyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine (121 mg, 65.8%):

¹ H-NMR (DMSO-d₆): δ0.87 (3H, t), 1.2-1.4 (6H, m), 1.40-1.46 (2H, m),2.30-2.37 (2H, m), 3.71 (3H, s), 5.83-5.90 (1H, m), 6.00 (2H, s), 6.42(5/6H, d), 6.49-6.56 (1/6H, m), 6.90 (2H, d), 7.19 (5/6H, d), 7.28 (2H,d), 7.38 (1/6H, d), 7.46 (1/6H, s), 7.49 (5/6H, s), 8.11 (1/6H, d), 8.14(5/6H, d), 11.37 (1H, s).

SIMS: m/z 445 (M⁺ +1).

(b) 1-(4-methoxybenzyl)-7-octyl-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine (1-8 mg, 89.2%):

¹ H-NMR (DMSO-d₆): δ0.84 (3H, t), 1.2-1.6 (12H, m), 2.59-2.64 (2H, m),3.71 (3H, s), 6.00 (2H, s), 6.90 (2H, d), 7.15 (1H, d), 7.28 (2H, d),7.36 (1H, s), 8.09 (1H, d), 11.25 (1H, s).

SIMS: m/z 447 (M⁺ +1).

(c) the title compound, 7-octyl-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine (55 mg, 70.1%):

¹ H-NMR (DMSO-d₆): δ0.85 (3H, t), 1.2-1.7 (12H, m), 2.60-2.65 (2H, m),7.17 (1H, d), 7.39 (1H, s), 7.50 (1H, d), 11.21 (1H, s).

SIMS: m/z 327 (M⁺ +1).

Example 16

7-(2-methoxycarbonyl-(E)-ethenyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine

(a) 7-formyl-3-(4-methoxybenzyl)-4(5H),10-dioxo-3H-1,2,3-triazolo 4,5-c!1!benzazepine (341 mg, 0.941 mmole) was suspended in toluene (60 ml),and methyl triphenylphosphoranylideneacetate (397 mg, 1.10 mmole) wasadded. After the reaction mixture was stirred at 80° C. for 6 hours, thesolvent was removed under reduced pressure. Crystalline deposits werecollected by filtration, pulverized with diethyl ether and desiccated togive7-(2-methoxycarbonyl-(E)-ethenyl)-3-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine (a-1: LP) as a yellow crystalline powder (288 mg,73.2%).

¹ H-NMR (DMSO-d₆): δ3.72 (3H, s), 3.76 (3H, s), 6.08 (2H, s), 6.72 (1H,d), 6.91 (2H, d), 7.31 (2H, d), 7.61 (1H, d), 7.72 (1H, d), 7.73 (1H,s), 8.23 (1H, d), 11.52 (1H, s).

Furthermore, starting from7-formyl-1-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine (150 mg, 0.414 mmole),7-(2-methoxycarbonyl-(E)-ethenyl)-1-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine (a-2: MP) was obtained as a yellow crystallinepowder (148 mg, 81.7%) in the same manner as described above.

¹ H-NMR (DMSO-d₆): δ3.76 (3H, s), 3.71 (3H, s), 5.99 (2H, s), 6.73 (1H,d), 6.90 (2H, d), 7.29 (2H, d), 7.59 (1H, d), 7.67 (1H, dd), 7.73 (1H,d), 8.17 (1H, d), 11.37 (1H, s).

EIMS: m/z 418 (M⁺).

(b) Anisole (15 ml) and trifluoroacetic acid (60 ml) were added to7-(2-methoxycarbonyl-(E)-ethenyl)-3-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine (a-1: LP) (1.50 g, 3.59 mmole), and the mixture wasstirred at 65° C. for 3 hours. After the solvent was removed underreduced pressure, crystalline deposits were collected by filtration,pulverized with diethyl ether and desiccated to give the title compound,7-(2-methoxycarbonyl-(E)-ethenyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c!1!benzazepine, as a yellow crystalline powder (866 mg, 80.9%).

¹ H-NMR (DMSO-d₆): δ3.76 (3H, s), 6.73 (1H, d), 7.60 (1H, s), 7.70 (1H,d), 7.76 (1H, s), 8.30 (1H, d), 11.42 (1H, s).

SIMS: m/z 299 (M⁺ +1).

Also, starting from7-(2-methoxycarbonyl-(E)-ethenyl)-1-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine (a-2: MP) (31.7 mg, 0.0758 mmole) obtained in thepreceding step (a), the same title compound as above can be obtained bydeprotection reaction in the same manner as above (21.8 mg, 96.5%).

Example 17

7-(2-methoxycarbonylethyl)-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine

(a)7-(2-methoxycarbonyl-(E)-ethenyl)-1-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo5,4-c! 1!benzoazepine (116 mg, 0.276 mmole) was dissolved in acetic acid(100 ml), 10% palladium on carbon (12 mg) was added, and the mixture wasstirred under the hydrogen atmosphere at room temperature for 14.5hours. After the reaction mixture was filtered through celite, thesolvent was removed under reduced pressure. Crystalline deposits werecollected by filtration, pulverized with diethyl ether and desiccated togive7-(2-methoxycarbonylethyl)-1-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine as a yellow crystalline powder (93.5 mg, 80.6%).

¹ H-NMR (DMSO-d₆): δ2.68 (2H, t), 2.90 (2H, t), 3.59 (3H, s), 3.71 (3H,s), 5.99 (2H, s), 6.90 (2H, d), 7.19 (1H, d), 7.28 (2H, d), 7.36 (1H,s), 8.09 (1H, d), 11.27 (1H, s).

SIMS: m/z 421 (M⁺ +1).

(b) Trifluoroacetic acid (4 ml) was added to7-(2-methoxycarbonylethyl)-1-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine (93.5 mg, 0.222 mmole), and the mixture was stirredat 60° C. for 4 hours. After the solvent was removed under reducedpressure, crystalline deposits were collected by filtration, pulverizedwith diethyl ether and desiccated to give the title compound,7-(2-methoxycarbonylethyl)-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine, as a yellow crystalline powder (64.8 mg, 97.2%).

¹ H-NMR (DMSO-d₆): δ2.70 (2H, t), 2.92 (2H, t), 3.60 (3H, s), 7.22 (1H,d), 7.41 (1H, s), 8.22 (1H, d), 11.33 (1H, s).

SIMS: m/z 301 (M⁺ +1).

Example 18

7-(2-methoxycarboxy-(E)-ethenyl)-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine

(a) A 1N aqueous sodium hydroxide solution (1.2 ml) was added to asolution of7-(2-methoxycarbonyl-(E)-ethenyl)-3-(4-methoxybenzyl)-4(5H),10-dioxo-3H-1,2,3-triazolo5,4-c! 1!benzoazepine (288 mg, 0.689 mmole) in tetrahydrofuran (10 ml),and the mixture was stirred at room temperature for 21 hours.Crystalline powder deposited during the reaction was collected byfiltration to give the sodium salt of7-(2-carboxy-(E)-ethenyl)-3-(4-methoxybenzyl)-4(5H),10-dioxo-3H-1,2,3-triazolo5,4-c! 1!benzoazepine (291 mg, 99.1%).

¹ H-NMR (DMSO-d₆): δ3.70 (3H, s), 6.16 (2H, s), 6.41 (1H, d), 6.87 (2H,d), 7.02 (1H, d), 7.05 (1H, d), 7.18 (1H, s), 7.29 (2H, d), 8.03 (1H,d).

(b) Anisole (3 ml) and trifluoroacetic acid (12 ml) were added to thesodium salt of7-(2-carboxy-(E)-ethenyl)-3-(4-methoxybenzyl)-4(5H),10-dioxo-3H-1,2,3-triazolo5,4-c! 1!benzoazepine (291 mg, 0.683 mmole) obtained in the precedingstep (a), and the mixture was stirred at 65° C. for 3 hours. The solventwas removed under reduced pressure. Precipitates were collected byfiltration, pulverized with diethyl ether and desiccated to give thetitle compound,7-(2-methoxycarboxy-(E)-ethenyl)-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine, as a yellow crystalline powder (146 mg, 75.2%).

¹ H-NMR (DMSO-d₆): δ6.63 (1H, d), 7.54 (1H, d), 7.67 (1H, d), 7.76 (1H,s), 8.30 (1H, d), 11.41 (1H, s), 12.73 (1H, s).

SIMS: m/z 285 (M⁺ +1).

Example 19

3:1 mixture of 7-(2-cyano-(E)-ethenyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine and7-(2-cyano-(Z)-ethenyl)-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine

The following compounds were obtained by the same procedures asdescribed in Example 16, except that methyltriphenylphosphoranylideneacetate was replaced bytriphenylphosphoranylideneacetonitrile.

(a) 3:1 mixture of7-(2-cyano-(E)-ethenyl)-3-(4-methoxybenzyl)-4(5H),10-dioxo-3H-1,2,3-triazolo5,4-c! 1!benzazepine and7-(2-cyano-(Z)-ethenyl)-3-(4-methoxybenzyl)-4(5H),10-dioxo-3H-1,2,3-triazolo5,4-c! 1!benzazepine as a yellow crystalline powder (166 mg, 79.2%);

¹ H-NMR (DMSO-d₆): δ3.72 (3H, s), 6.07 (2H, s), 6.13 (1/4H, d), 6.57(3/4H, s), 6.90 (2H, d), 7.31 (2H, d), 7.50 (1/4H, d), 7.63-7.74 (7/4H,m), 7.71 (3/4H, d), 7.80 (1/4H, s), 8.24 (3/4H, d), 8.31 (1/4H, d),11.60 (3/4H, s), 11.71 (1/4H, s).

(b) 3:1 mixture of the title compounds,7-(2-cyano-(E)-ethenyl)-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine and7-(2-cyano-(Z)-ethenyl)-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine as a yellow crystalline powder (79.8 mg, 83.4%);

¹ H-NMR (DMSO-d₆): δ6.12 (1/4H, d), 6.55 (3/4H, d), 7.48 (1/4H, d), 7.61(3/4H, d), 7.65-7.71 (1H, m), 7.79 (1/4H, s), 8.29 (3/4H, d), 8.36(1/4H, d), 11.46 (3/4H, s), 11.59 (1/4H, s).

FDMS: m/z 265 (M⁺).

Example 20

7-(3-oxo-(E)-butenyl)-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine

The following compounds were obtained by the same procedures asdescribed in Example 16, except that methyltriphenylphosphoranylideneacetate was replaced bytriphenylphosphoranylidene-2-propanone.

(a)7-(3-oxo-(E)-butenyl)-3-(4-methoxybenzyl)-4(5H),10-dioxo-3H-1,2,3-triazolo5,4-c! 1!benzazepine as a yellow crystalline powder (171 mg, 80.2 mg);

¹ H-NMR (DMSO-d₆): δ2.38 (3H, s), 3.72 (3H, s), 6.07 (2H, s), 6.86 (1H,d), 6.91 (2H, d), 7.31 (2H, d), 7.58 (1H, d), 7.68 (1H, d), 7.75 (1H,s), 8.25 (1H, d), 11.55 (1H, s).

SIMS: m/z 403 (M⁺ +1).

(b) the title compound,7-(3-oxo-(E)-butenyl)-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine as a yellow crystalline powder (105 mg, 87.5%);

¹ H-NMR (DMSO-d₆): δ2.39 (3H, s), 6.87 (1H, d), 7.58 (1H, d), 7.67 (1H,d), 7.80 (1H, s), 8.32 (1H, d), 11.43 (1H, s).

Example 21

7-isopropyl-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c! 1!benzazepine

(a) 7-formyl-1-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine (29.6 mg, 0.0817 mmole) was suspended into tetrahydrofuran(4 ml) at -78° C. under the argon atmosphere, and 1.06N methylmagnesiumbromide (0.1 ml, 0.106 mmole) was added. After stirring at roomtemperature for 2 hours, the reaction mixture was cooled again to -78°C., and an additional amount of 1.06N methylmagnesium bromide (0.125 ml,0.133 mmole) was added. After stirring the reaction mixture at roomtemperature for further 14.5 hours, a saturated aqueous ammoniumchloride solution was added, and the reaction mixture was extracted withethyl acetate. The organic layer was washed with a saturated aqueoussaline and dried over anhydrous magnesium sulfate, and the solvent wasremoved under reduced pressure. The residue thus obtained was purifiedby silica gel column chromatography (chloroform:methanol=10:1) to give7-(1-hydroxyethyl)-1-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine as a yellow crystalline powder (29 mg, 93.8 mmole).

¹ H-NMR (DMSO-d₆): δ1.33 (3H, d), 3.71 (3H, s), 4.76(1H, m), 5.45 (1H,d), 5.99 (2H, s), 6.90 (2H, d), 7.27 (1H, d), 7.28 (2H, d), 7.75 (1H,s), 8.12 (1H, d), 11.31 (1H, s).

SIMS: m/z 379 (M⁺ +1).

(b)7-(1-hydroxyethyl)-1-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine (87 mg, 0.230 mmole) was dissolved in acetone (40ml), and active manganese dioxide (249 mg) was added. After stirring thereaction mixture at room temperature for 3 hours, an additional amountof active manganese dioxide (490 mg) was added, and the reaction mixturewas further stirred for 14.5 hours. The reaction mixture was filteredthrough celite, and the filtrate was concentrated under reducedpressure. Precipitates were collected by filtration to give7-acetyl-1-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo 4.5-c!1!benzazepine (77.5 mg, 89.5%).

¹ H-NMR (DMSO-d₆): δ2.62 (3H, s), 3.71 (3H, s), 5.98 (2H, s), 6.91 (2H,d), 7.30 (2H, d), 7.77 (1H, dd), 8.15 (1H, d), 8.26 (1H, d), 11.47 (1H,s).

(c) Methyltriphosphonium bromide (162 mg, 0.453 mmole) was suspended intetrahydrofuran at 0° C. under the argon atmosphere, and potassiumtert-butoxide (48.1 mg, 0.429 mmole) was added. After stirring themixture at room temperature for 15 minutes, a solution of7-acetyl-1-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo 4.5-c!1!benzazepine (27.7 mg, 0.0736 mmole) in N,N-dimethylformamide (1 ml)was added, and resulting mixture was further stirred at room temperaturefor 1 hour. After the reaction mixture was diluted with water, it wasextracted with ethyl acetate, and the organic layer was washed with asaturated aqueous saline.

The organic layer was dried over anhydrous sodium sulfate, and thesolvent was removed under reduced pressure. The residue thus obtainedwas purified by silica gel column chromatography(chloroform:methanol=40:1) to give7-isopropenyl-1-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c!1!benzazepine (16.0 mg, 58.1%).

¹ H-NMR (DMSO-d₆): δ2.13 (3H, s), 3.71 (3H, s), 5.34 (1H, s), 5.65 (1H,s), 6.00 (2H, s), 6.90 (2H, d), 7.29 (2H, d), 7.49 (1H, d), 7.70 (1H,s), 8.14 (1H, d), 11.29 (1H, s).

SIMS: m/z 375 (M⁺ +1).

(d) 7-isopropenyl-1-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c!1!benzazepine (186 mg, 0.497 mmole) was dissolved in acetic acid(250 ml), 10% palladium on carbon (21.2 mg) was added, and the mixturewas stirred under the hydrogen atmosphere at room temperature for 29hours. After the reaction mixture was filtered through celite, thesolvent was removed under reduced pressure. Precipitates was collectedby filtration, pulverized with diethyl ether and desiccated to give7-isopropyl-1-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine as a yellow crystalline powder (127 mg, 67.9%).

¹ H-NMR (DMSO-d₆): δ1.22 (6H, d), 2.93 (1H, q), 3.71 (3H, s), 6.00 (2H,s), 6.90 (2H, d), 7.22 (1H, d), 7.28 (2H, d), 7.43 (1H, s), 8.11 (1H,d), 11.26 (1H, s).

SIMS: m/z 377 (M⁺ +1).

(e) Anisole (1 ml) and trifluoroacetic acid (4 ml) were added to7-isopropyl-1-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine (127 mg, 0.337 mmole), and the mixture was stirred at 60°C. for 2 hours. The solvent was removed under reduced pressure.Precipitates were collected by filtration, pulverized with diethyl etherand desiccated to give the title compound,7-isopropyl-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c! 1!benzazepine as ayellow crystalline powder (79 mg, 91.5%).

¹ H-NMR (DMSO-d₆): δ1.23 (6H, s), 2.92 (1H, q), 7.21 (1H, d), 7.45 (1H,s), 8.22 (1H, d), 11.06 (1H, s).

SIMS: m/z 257 (M⁺ +1).

Example 22

7-acetyl-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c! 1!benzazepine

Anisole (1 ml) and trifluoroacetic acid (4 ml) were added to7-acetyl-1-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine (107 mg, 0.284 mmole), and the mixture was stirred at 60°C. for 2 hours. The solvent was removed under reduced pressure.Precipitates were collected by filtration, pulverized with diethyl etherand desiccated to give the title compound,7-acetyl-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c! 1!benzazepine as ayellow crystalline powder (73 mg, 100%).

¹ H-NMR (DMSO-d₆): δ2.63 (3H, s), 7.80 (2H, d), 8.19 (1H, d), 8.39 (1H,d), 11.55 (1H, s).

SIMS: m/z 257 (M⁺ +1).

Example 23

7-methoxymethyl-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c! 1!benzazepine

(a) To a solution of1-(4-methoxybenzyl)-7-dimethoxymethyl-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine (409 mg, 1.0 mmole) in acetic acid (40 ml) wasadded 10% palladium on carbon (40 mg), and the mixture was stirred underthe hydrogen atmosphere at room temperature for 20 hours. After thereaction mixture was filtered through celite, the filtrate wasconcentrated under reduced pressure. Solids thus obtained was dissolvedin tetrahydrofuran (60 ml), 1N hydrochloric acid (10 ml) was added, andthe mixture was stirred at room temperature for 16 hours. After thereaction mixture was extracted with ethyl acetate, the organic layer waswashed with a saturated aqueous sodium hydrogen carbonate solution and asaturated aqueous saline, and dried over anhydrous magnesium sulfate,and the solvent was removed under reduced pressure.

Residues thus obtained was treated with hydrochloric acid and thenextracted with ethyl acetate. The organic layer was washed with asaturated aqueous sodium hydrogen carbonate solution and a saturatedaqueous saline, and dried over anhydrous magnesium sulfate. The solventwas removed under reduced pressure. Residue thus obtained was purifiedby silica gel column chromatography (chloroform:methanol=20:1) to give1-(4-methoxybenzyl)-7-methoxymethyl-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine (68 mg, 18.0%) as a yellow powder and7-formyl-1-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine (265 mg, 73.2%) as a yellow crystalline powder.

1-(4-methoxybenzyl)-7-methoxymethyl-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine;

¹ H-NMR (DMSO-d₆): δ3.34 (3H, s), 3.71 (3H, s), 4.49 (2H, s), 5.99 (2H,s), 6.90 (2H, d), 7.22 (1H, d), 7.28 (2H, d), 7.49 (1H, s), 8.15 (1H,d), 11.55 (1H, s).

EIMS: m/z 378 (M⁺).

(b) Anisole (0.25 ml) and trifluoroacetic acid (1 ml) were added to1-(4-methoxybenzyl)-7-methoxymethyl-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine (28 mg, 0.0743 mmole), and the mixture was stirredat 60° C. for 1 hour. The reaction mixture was concentrated underreduced pressure. Precipitates obtained were pulverized with ethylacetate and desiccated to give the title compound,7-methoxymethyl-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c! 1!benzazepine asa yellow crystalline powder (17.6 mg, 91.7%).

¹ H-NMR (DMSO-d₆): δ3.35 (3H, s), 4.51 (2H, s), 7.25 (1H, d), 7.53 (1H,s), 8.28 (1H, d), 11.38 (1H, s).

SIMS: m/z 259 (M⁺ +1).

Example 24

7-methoxycarbonyl-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c! 1!benzazepine

(a) To a solution of tert-butyl propiolate (3.54 ml, 25.81 mmole) intetrahydrofuran (60 ml) was added at -70° C. under the argon atmospherea solution of 2.0M lithium diisopropylamide in aheptane-tetrahydrofuran-ethylbenzene mixture (13.0 ml, 26 mmole), andthe mixture was stirred for 30 minutes. The reaction mixture was thenadded to a solution of 4-methoxycarbonyl-2-nitrobenzaldehyde (4.5 g,21.5 mmole) in tetrahydrofuran (100 ml), and the mixture was furtherstirred at -75° C. for 5 minutes. After a solution of acetic acid (3.2ml, 53.3 mmole) in tetrahydrofuran (10 ml) and water were added, thereaction mixture was extracted with ethyl acetate (400 ml). The organiclayer was washed with dilute hydrochloric acid, a saturated aqueoussodium hydrogen carbonate solution and a saturated aqueous saline inthis sequence. After the organic layer was dried over anhydrousmagnesium sulfate, the solvent was removed under reduced pressure togive the crude product of tert-butyl4-hydroxy-4-(4-methoxycarbonyl-6-nitrophenyl)-2-butynoate as a brown oil(7.655 g).

To a solution of tert-butyl4-hydroxy-4(4-methoxycarbonyl-6-nitrophenyl)-2-butynoate (7.655 g) thusobtained in toluene (100 ml) was added 4-methoxybenzylazide (6.52 g,40.0 mmole), and the mixture was stirred under heating at 100° C. for 6hours. After the reaction mixture was cooled to room temperature, it wasconcentrated under reduced pressure. The residue thus obtained waspurified by silica gel column chromatography (hexane:ethyl acetate=2:1)to give a 3:2 mixture of tert-butyl4(hydroxy-(4-methoxycarbonyl-2-nitrophenyl)methyl)-1-(4-methoxybenzyl)-1,2,3-triazole-5-carboxylate(a-1: low polar product (LP)), and tert-butyl5-(hydroxy-(4-methoxycarbonyl-6-nitrophenyl)methyl)-1-(4-methoxybenzyl)-1,2,3-triazole-4-carboxylate(a-2: highly polar product (MP)) as a brown oil (4.22 g, 42.3%).

3:2 mixture of a-1 (LP) and a-2 (MP);

¹ H-NMR (CDCl₃): δ1.54 (18/5H, s), 1.56 (27/5H, s), 3.63 (6/5H, s), 3.78(9/5H, s), 3.95 (6/5H, s), 3.98 (9/5H, s), 5.46 (2/5H, d), 5.73 (3/5H,d), 5.80 (4/5H, d), 6.45 (2/5H, d), 6.55 (2/5H, d), 6.84 (3/5H, d), 6.92(6/5H, d), 7.02 (4/5H, d), 7.16 (6/5H, d), 7.76 (1H, dd), 8.11 (3/5H,d), 8.34 (2/5H, d), 8.36 (2/5H, d), 8.39 (3/5H, d), 8.71 (3/5H, d).

SIMS: m/z 499 (M⁺ +1).

(b) To a solution of the 3:2 mixture (4.65 g, 9.33 mmole) of thecompounds a-1 and a-2 obtained in the preceding step (a) in methylenechloride (100 ml) was added manganese dioxide (12 g) in two portions,and the mixture was stirred at room temperature for 6 hours. After thereaction mixture was filtered through celite and washed with methylenechloride, the solvent was removed under reduced pressure. The residueobtained was purified by silica gel column chromatography (hexane:ethylacetate=4:1-2:1) to give tert-butyl1-(4-methoxybenzyl)-4(4-methoxycarbonyl)-6-nitrobenzoyl)-1,2,3-triazole-5-carboxylate(b-1: LP) (2.16 g, 46.6%) as a pale brown oil from the fractions elutedwith hexane:ethyl acetate=4:1, and tert-butyl1-(4-methoxybenzyl)-5-(4-methoxycarbonyl)-6-nitrobenzoyl)-1,2,3-triazole-4-carboxylate(b-2: MP) (0.68 g, 14.7%) as a pale brown crystalline powder from thefractions eluted with hexane:ethyl acetate=4:1-2:1.

b-1 (LP);

¹ H-NMR (CDCl₃): δ1.57 (9H, s), 3.79 (3H, s), 4.01 (3H, s), 5.70 (2H,s), 6.86 (2H, d), 7.25 (2H, d), 7.67 (1H, d), 8.41 (1H, dd), 8.82 (1H,d).

SIMS: m/z 497 (M⁺ +1).

b-2 (MP);

¹ H-NMR (CDCl₃): δ1.31 (9H, s), 3.78 (3H, s), 4.01 (3H, s), 5.85 (2H,s), 6.85 (2H, d), 7.35 (2H, d), 7.37 (1H, d), 8.30 (1H, dd), 8.67 (1H,d).

SIMS: m/z 497 (M⁺ +1).

(c) Trifluoroacetic acid (6.1 ml, 79.2 mmole) was added to a solution oftert-butyl1-(4-methoxybenzyl)-4(4-methoxycarbonyl)-6-nitrobenzoyl)-1,2,3-triazole-5-carboxylate(b-1) (1.96 g, 3.95 mmole) obtained in the preceding step (b) inmethylene chloride (20 ml), and the mixture was stirred underice-cooling for 30 minutes and at 5°-10° C. for 30 minutes. The reactionmixture was diluted with ethyl acetate (100 ml) and cold water (80 ml).The organic layer was washed with water and then extracted with asaturated aqueous sodium hydrogen carbonate solution (150 ml). Theaqueous layer was then acidified with hydrochloric acid and extractedwith ethyl acetate (400 ml). The extract layer was washed with water anda saturated aqueous saline, and dried over anhydrous magnesium sulfate.The solvent was removed under reduced pressure, and diethyl ether wasadded. Precipitates were collected by filtration to give1-(4-methoxybenzyl)-4(4-methoxycarbonyl-6-nitrobenzoyl)-1,2,3-triazole-5-carboxylicacid (c-1': LP) as a colorless crystalline powder (1.51 g, 86.8%).

c-1' (LP);

¹ H-NMR (CDCl₃): δ3.74 (3H, s), 3.96 (3H, s), 5.71 (2H, s), 6.92 (2H,d), 7.23 (2H, d), 7.89 (1H, d), 8.43 (1H, dd), 8.61 (1H, d).

SIMS: m/z 441 (M⁺ +1).

This product (c-1') (1.48 g, 3.36 mmole) was next dissolved in a mixtureof ethanol (40 ml) and ethyl acetate (40 ml), 10% palladium on carbon(180 mg) was added, and the mixture was stirred under the hydrogenatmosphere at room temperature for 7 hours. After the reaction mixturewas filtered through celite, the filtrate was concentrated under reducedpressure. The mixture of diethyl ether:isopropyl ether=1:1 (20 ml) wasadded, and precipitates were collected by filtration to give4(2-amino-4-methoxycarbonylbenzoyl)-1-(4-methoxybenzyl)-1,2,3-triazole-5-carboxylicacid (c-1: LP) as an orange crystalline powder (1.307 g, 94.8%).

c-1 (LP);

¹ H-NMR (CDCl₃): δ3.78 (3H, s), 3.94 (3H, s), 6.05 (2H, s), 6.86 (2H,d), 7.31 (1H, dd), 7.42 (1H, d), 7.45 (2H, d), 8.70 (1H, d).

SIMS: m/z 411 (M⁺ +1).

Similarly, to a solution of tert-butyl1-(4-methoxybenzyl)-5-(4-methoxycarbonyl)-6-nitrobenzoyl)-1,2,3-triazole-4-carboxylate(b-2) (660 mg, 1.33 mmole) obtained in the preceding step (b) inmethylene chloride (7 ml) was added trifluoroacetic acid (2.05 ml, 26.6mmole), and the mixture was stirred under ice-cooling for 1 hour and at10°-15° C. for further 3 hours.

The reaction mixture was diluted with ethyl acetate (80 ml) and coldwater (50 ml). The organic layer was washed with water, a saturatedaqueous sodium hydrogen carbonate solution and a saturated aqueoussaline, and dried over anhydrous magnesium sulfate, and the solvent wasremoved under reduced pressure. Diethyl ether was added, andprecipitates were collected by filtration to give1-(4-methoxybenzyl)-5-(4-methoxycarbonyl-6-nitrobenzoyl)-1,2,3-triazole-4-carboxylicacid (c-2': MP) as a pale brown powder (360 mg, 61.5%).

c-2' (MP);

¹ H-NMR (DMSO-d₆): δ3.74 (3H, s), 3.96 (3H, s), 5.71 (2H, s), 6.92 (2H,d), 7.23 (2H, d), 7.88 (1H, d), 8.43 (1H, dd), 8.62 (1H, d).

SIMS: m/z 441 (M⁺ +1).

In the same way as above, the compound (c-2') (343 mg, 0.779 mmole) wasdissolved in ethyl acetate (15 ml) and reduced under the hydrogenatmosphere in the presence of 10% palladium on carbon (35 mg) at roomtemperature for 8.5 hours to give5-(2-amino-4-methoxycarbonylbenzoyl)-1-(4-methoxybenzyl)-1,2,3-triazole-4-carboxylicacid (c-2: MP) (312 mg, 97.6%).

c-2 (MP);

¹ H-NMR (CDCl₃): δ3.78 (3H, s), 3.94 (3H, s), 6.06 (2H, s), 6.86 (2H,d), 7.31 (1H, dd), 7.44 (1H, m), 7.45 (2H, d), 8.73 (1H, d).

SIMS: m/z 410 (M⁺).

(d) Under the argon atmosphere, to a solution of4(2-amino-4-methoxycarbonylbenzoyl)-1-(4-methoxybenzyl)-1,2,3-triazole-5-carboxylicacid (c-1) (410 mg, 1.0 mmole) in methylene chloride (10 ml) were addedunder ice-cooling tributylamine (262 μl, 1.1 mmole),2-chloro-1-methylpyridinium p-toluenesulfonate 360 mg, 1.2 mmole) and3,4-dihydro-2H-pyrido 1,2-a!pyrimidin-2-one (185 mg, 1.25 mmole) in thissequence, and the mixture was stirred at room temperature for 5 hours.

The reaction mixture was diluted with methylene chloride and water, andthe mixture was stirred under ice-cooling for 15 minutes. Precipitateswere collected by filtration, washed with water, a saturated aqueoussodium hydrogen carbonate solution and a saturated aqueous saline, anddesiccated to give3-(4-methoxybenzyl)-7-methoxycarbonyl-4(5H),10-dioxo-3H-1,2,3-triazolo5,4-c! 1!benzazepine (d-1: LP) as a pale yellow powder (100 mg, 25.5%).

d-1 (LP);

¹ H-NMR (DMSO-d₆): δ3.72 (3H, s), 3.91 (3H, s), 6.08 (2H, s), 6.90 (2H,d), 7.32 (2H, d), 7.80 (1H, d), 8.20 (1H, s), 8.33 (1H, d), 11.66 (1H,s).

FDMS: m/z 392 (M⁺).

(e) Anisole (0.2 ml) and trifluoroacetic acid (2.0 ml) were added to3-(4-methoxybenzyl)-7-methoxycarbonyl-4(5H),10-dioxo-3H-1,2,3-triazolo5.4-c! 1!benzazepine (d-1) (90 mg, 0.23 mmole), and the mixture wasstirred at 60° C. for 1.5 hours. The solvent was removed under reducedpressure. The residue was pulverized with diisopropyl ether anddesiccated to give the title compound,7-methoxycarbonyl-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c! 1!benzazepineas a pale yellow powder (65 mg, 100%).

¹ H-NMR (DMSO-d₆): δ3.91 (3H, s), 7.79 (1H, dd), 8.25 (1H, d), 8.39 (1H,d), 11.60 (1H, brs).

SIMS: m/z 273 (M⁺ -1).

Example 25

7-hydroxy-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c! 1!benzazepine

(a) 1.5N butyllithium (19.3 ml, 29.0 mmole) was added under the argonatmosphere to a solution of diisopropylamine (4.3 ml, 30.6 mmole) intetrahydrofuran (50 ml) at -78° C., and the mixture was stirred for 1hour. Next, ethyl propiolate (2.4 ml, 23.7 mmole) and a solution of4-methoxymethoxy-2-nitrobenzaldehyde (3.6 g, 17.0 mmole) intetrahydrofuran (35 ml) were added in this sequence, and the reactionmixture was stirred at -78° C. for further 2 hours. After a solution ofacetic acid (5.0 ml, 87.5 mmole) in tetrahydrofuran (20 ml) and waterwere sequentially added, the reaction mixture was extracted with ethylacetate. The organic layer was washed with dilute hydrochloric acid,water, a saturated aqueous sodium hydrogen carbonate solution and asaturated aqueous saline in this sequence. After the organic layer wasdried over anhydrous magnesium sulfate, the solvent was removed underreduced pressure to give ethyl4-hydroxy-4(4-methoxymethoxy-2-nitrophenyl)-2-butynoate as an oil (5.53g).

Ethyl 4-hydroxy-4(4-methoxymethoxy-2-nitrophenyl)-2-butynoate thusobtained was dissolved in toluene (60 ml), 4-methoxybenzylazide (8.3 g,50.9 mmole) was added, and the mixture was stirred under heating at 100°C. overnight. After the reaction mixture was cooled to room temperature,it was purified by silica gel column chromatography (hexane:ethylacetate=2:1) to give a 1:1 mixture (6.20 g, 77%) of ethyl4(hydroxy-(4-methoxymethoxy-2-nitrophenyl)methyl)-1-(4-methoxybenzyl)-1,2,3-triazole-5-carboxylate(a-1: low polar product (LP)), and ethyl5-(hydroxy-(4-methoxymethoxy-2-nitrophenyl)methyl)-1-(4-methoxybenzyl)-1,2,3-triazole-4-carboxylate(a-2: highly polar product (MP)).

The 1:1 mixture of a-1 (LP) and a-2 (MP):

¹ H-NMR (CDCl₃): δ1.34 (3/2H, t), 1.40 (3/2H, t), 3.46 (3/2H, s), 3.49(3/2H, s), 3.64 (1/2H, s), 3.70 (3/2H, s), 3.78 (3/2H, s), 4.35-4.45(2H, m), 5.15 (1H, s), 5.23 (1H, s), 5.43 (1/2H, d), 5.50 (1/2H, d),5.68 (1/2H, d), 5.78 (1/2H, d), 5.83 (1/2H, d), 6.37 (1/2H, d), 6.63(1H, d), 6.80 (1/2H, d), 6.78-6.88 (4H, m), 7.06 (1H, d), 7.22 (1H, d),7.34 (1/2H, dd), 7.50 (1/2H, d), 7.70 (1/2H, d), 7.81 (1/2H, d).

EIMS: m/z 472 (M⁺ +1).

(b) Manganese dioxide (18 g) was added to a solution of the 1:1 mixture(6.00 g, 12.7 mmole) of the compounds a-1 and a-2 in methylene chloride(120 ml), and the mixture was stirred at room temperature overnight.After the reaction mixture was filtered through celite and washed withethyl acetate, the solvent was removed under reduced pressure. Theresidue thus obtained was purified by silica gel column chromatography(hexane:ethyl acetate=2:1-1:1) to give ethyl1-(4-methoxybenzyl)-4(4-methoxymethoxy-2-nitrobenzoyl)-1,2,3-triazole-5-carboxylate(b-1: LP) as a brown oil (2.55 g, 43%) from the fractions eluted withhexane:ethyl acetate=2:1, and ethyl1-(4-methoxybenzyl)-5-(4-methoxymethoxy-2-nitrobenzoyl)-1,2,3-triazole-4-carboxylate(b-2: MP) as a brown crystalline powder (3.16 g, 53%) from the fractionseluted with hexane:ethyl acetate=1:1.

b-1 (LP);

¹ H-NMR (CDCl₃): δ1.35 (3H, t), 3.51 (3H, s), 3.79 (3H, s), 4.40 (2H,s), 5.29 (2H, s), 5.72 (2H, s), 6.86 (2H, d), 7.24 (2H, d), 7.37 (1H,dd), 7.60 (1H, d), 7.76 (1H, d).

EIMS: m/z 470 (M⁺).

b-2 (MP);

¹ H-NMR (CDCl₃): δ1.14 (3H, t), 3.49 (3H, s), 3.76 (3H, s), 4.11 (2H,q), 5.26 (2H, s), 5.72 (2H, s), 6.82 (2H, d), 7.17-7.24 (2H, m), 7.32(2H, d), 7.54 (1H, d).

EIMS: m/z 470 (M⁺).

(c) A 1N aqueous sodium hydroxide solution (11 ml) was added to asolution of ethyl1-(4-methoxybenzyl)-4(4-methoxymethoxy-2-nitrobenzoyl)-1,2,3-triazole-5-carboxylate(b-1) (2.55 g, 5.42 mmole) obtained in the preceding step (b) intetrahydrofuran (50 ml), and the mixture was stirred at room temperaturefor 2 hours. The reaction mixture was diluted with ether, and water wasadded. After the aqueous layer was acidified with hydrochloric acid, itwas extracted with ethyl acetate, and washed with water and a saturatedaqueous saline.

After the organic layer was dried over anhydrous magnesium sulfate, thesolvent was removed under reduced pressure to give1-(4-methoxybenzyl)-4(4-methoxymethoxy-2-nitrobenzoyl)-1,2,3-triazole-5-carboxylicacid (c-1': LP) (2.23 g, 93%). A 2.18 g (4.93 mmole) portion of theproduct was then dissolved in a mixed solvent of ethanol (100 ml) andethyl acetate (50 ml), 10% palladium on carbon (262 mg) was added, andthe mixture was stirred under the hydrogen atmosphere at roomtemperature for 5 hours. The reaction mixture filtered through celite,and the filtrate was concentrated under reduced pressure to give4(2-amino-4-methoxymethoxybenzoyl)-1-(4-methoxybenzyl)-1,2,3-triazole-5-carboxylicacid (c-1: LP) (1.88 g, 93%).

c-1' (LP);

¹ H-NMR (CDCl₃): δ3.53 (3H, s), 3.77 (3H, s), 5.32 (2H, s), 6.02 (2H,s), 6.84 (2H, d), 7.39 (2H, d), 7.43 (1H, dd), 7.58 (1H, d), 7.88 (1H,d), 14.10 (1H, brs).

SIMS: m/z 443 (M⁺ +1).

c-1 (LP);

¹ H-NMR (CDCl₃): δ3.49 (3H, s), 3.78 (3H, s), 5.22 (2H, s), 6.04 (2H,s), 6.31 (1H, d), 6.42 (1H, dd), 6.50 (2H, brs), 6.86 (2H, d), 7.45 (2H,d), 8.74 (1H, d).

SIMS: m/z 413 (M⁺ +1)

In the same manner as above, a solution of ethyl1-(4-methoxybenzyl)-5-(4-methoxymethoxy-2-nitrobenzoyl)-1,2,3-triazole-4-carboxylate(b-2) (3.16 g, 6.72 mmole) in tetrahydrofuran (50 ml) was hydrolyzedwith a 1N aqueous sodium hydroxide solution (13 ml) at room temperaturefor 3 hours to give1-(4-methoxybenzyl)-5-(4-methoxymethoxy-2-nitrobenzoyl)-1,2,3-triazole-4-carboxylicacid (c-2': MP) (2.22 g, 75%)

Furthermore, a 2.19 g portion (4.95 mmole) of the product dissolved in amixed solvent of ethanol (100 ml) and ethyl acetate (100 ml) was reducedin the presence of 10% palladium on carbon (263 mg) under the hydrogenatmosphere at room temperature overnight to give5-(2-amino-4-methoxymethoxybenzoyl)-1-(4-methoxybenzyl)-1,2,3-triazole-4-carboxylicacid (c-2: MP) (1.95 g, 96%).

c-2' (MP);

¹ H-NMR (CDCl₃): δ3.49 (3H, s), 3.78 (3H, s), 5.27 (2H, s), 5.74 (2H,s), 6.86 (2H, d), 7.29 (1H, dd), 7.36 (1H, d), 7.40 (2H, d), 7.60 (1H,d), 8.74 (1H, d).

SIMS: m/z 443 (M⁺ +1).

c-2 (MP);

¹ H-NMR (CDCl₃): δ3.46 (3H, s), 3.69 (3H, s), 5.14 (2H, s), 5.30-5.60(2H, brs), 6.01 (1H, dd), 6.26 (1H, d), 6.59 (1H, d), 6.68 (2H, d), 7.07(2H, d).

SIMS: m/z 413 (M⁺ +1).

(d) Under the argon atmosphere, to a solution of4(2-amino-4-methoxymethoxybenzoyl)-1-(4-methoxybenzyl)-1,2,3-triazole-5-carboxylicacid (c-1) (1.88 g, 4.56 mmole) in methylene chloride (50 ml) were addedunder ice-cooling tributylamine (1.14 ml, 4.78 mmole),2-fluoro-1-methylpyridinium p-toluenesulfonate (1.42 g, 5.01 mmole) and3,4-dihydro-2H-pyrido 1,2-a!pyrimidin-2-one (810 mg, 5.47 mmole) in thissequence, and the mixture was stirred under ice-cooling for 20 minutesand at room temperature overnight.

The reaction mixture was diluted with water, and precipitates werecollected by filtration, washed with methylene chloride followed bywater, and desiccated to give3-(4-methoxybenzyl)-7-methoxymethoxy-4(5H),10-dioxo-3H-1,2,3-triazolo5.4-c! 1!benzazepine (d-1: LP) as a pale yellow crystalline powder (1.02g, 57%).

d-1 (LP);

¹ H-NMR (DMSO-d₆): δ3.39 (3H, s), 3.72 (3H, s), 5.29 (2H, s), 6.08 (2H,s), 6.90 (2H, d), 7.03 (1H, dd), 7.15 (1H, d), 7.30 (2H, d), 8.22 (1H,d), 11.42 (1H, s).

SIMS: m/z 395 (M⁺ +1).

In the same manner as above, starting from5-(2-amino-4-methoxymethoxybenzoyl)-1-(4-methoxybenzyl)-1,2,3-triazole-4-carboxylicacid (c-2) (1.95 g, 4.72 mmole),1-(4-methoxybenzyl)-7-methoxymethoxy-4(5H),10-dioxo-1H-1,2,3-triazolo5.4-c! 1!benzazepine (d-2: MP) (1.25 g, 67%).

d-2 (MP);

¹ H-NMR (DMSO-d₆): δ3.39 (3H, s), 3.71 (3H, s), 5.29 (2H, s), 5.76 (2H,s), 6.90 (2H, d), 6.99 (1H, dd), 7.14 (1H, d), 7.27 (2H, d), 8.14 (1H,d), 11.28 (1H, s).

SIMS: m/z 395 (M⁺ +1).

(e) To a solution of3-(4-methoxybenzyl)-7-methoxymethoxy-4(5H),10-dioxo-3H-1,2,3-triazolo5.4-c! 1!benzazepine (d-1) (901 mg, 2.28 mmole) in methylene chloride(25 ml) was added trifluoroacetic acid (1.8 ml), and the mixture wasstirred at room temperature overnight. The reaction mixture was dilutedwith methylene chloride, and the resulting precipitates were collectedby filtration and desiccated to give7-hydroxy-1-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine (e) as a pale powder (737 mg, 92%).

¹ H-NMR (DMSO-d₆): δ3.71 (3H, s), 6.01 (2H, s), 6.74 (1H, dd ), 6.87(1H, d), 6.89 (2H, d), 7.26 (2H, d), 8.09 (1H, d), 10.91 (1H, s), 11.23(1H, s).

Also, a solution of1-(4-methoxybenzyl)-7-methoxymethoxy-4(5H),10-dioxo-1H-1,2,3-triazolo5,4-c! 1!benzazepine (d-2) (1.11 g, 2.81 mmole) obtained in thepreceding step (d) in methylene chloride (30 ml) was subjected todeprotection with trifluoroacetic acid (2.1 ml) and post-treatment inthe same way as above to give the same compound (e) (847 mg, 86%).

¹ H-NMR (DMSO-d₆): δ3.70 (3H, s), 6.01 (2H, s), 6.74 (1H, dd), 6.86 (1H,d), 6.89 (2H, d), 7.26 (2H, d), 8.09 (1H, d), 10.91 (1H, s), 11.23 (1H,s).

EIMS: m/z 350 (M⁺).

(f) Anisole (0.3 ml) and trifluoroacetic acid (3.0 ml) were added to7-hydroxy-1-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine (e) (100 mg, 0.285 mmole), and the mixture was stirred at60° C. for 1.5 hours. The solvent was then removed under reducedpressure. The resulting precipitates were pulverized with diethyl etherand desiccated to give the title compound,7-hydroxy-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c! 1!benzazepine as awhite powder (51 mg, 78%).

¹ H-NMR (DMSO-d₆): δ6.77 (1H, dd), 6.91 (1H, d), 8.20 (1H, d), 10.85(1H, s), 11.26 (1H, s).

SIMS: m/z 231 (M⁺ +1).

Example 26

7-methoxy-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c! 1!benzazepine

(a) 7-hydroxy-1-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine obtained in Example 25 (e) was dissolved in a mixedsolvent of acetone (1 ml) and N,N-dimethylformamide (0.8 ml). Potassiumcarbonate (14 mg, 0.101 mmole) and methyl iodide (0.008 ml, 0.129 mmole)were added to the solution, and the mixture was stirred at roomtemperature for 4 hours. The reaction mixture was diluted with water,and the resulting precipitates were collected by filtration anddesiccated to give7-methoxy-1-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine (20 mg, 65%).

¹ H-NMR (DMSO-d₆): δ3.71 (3H, s), 3.85 (3H, s), 6.01 (2H, s), 6.90 (2H,d), 6.93 (1H, dd), 7.08 (1H, d), 7.27 (2H, d), 8.16 (1H, d), 11.26 (1H,s).

SIMS: m/z 365 (M⁺ +1).

(b) Anisole (0.05 ml) and trifluoroacetic acid (2.0 ml) were added to7-methoxy-1-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine (a) (95 mg, 0.261 mmole), and the mixture was stirred at60° C. for 3 hours. The solvent was removed under reduced pressure. Theresulting precipitates were collected by filtration, washed withmethylene chloride and water, desiccated to give the title compound,7-methoxy-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c! 1!benzazepine as apale yellow powder (54 mg, 85%).

¹ H-NMR (DMSO-d₆): δ3.86 (3H, s), 6.96 (1H, dd), 7.12 (1H, d), 8.27 (1H,d), 11.29 (1H, s).

SIMS: m/z 245 (M⁺ +1).

The compounds in the following examples 27-38 were synthesized startingfrom 7-hydroxy-1-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine obtained in Example 25 (e) in the same manner as inExample 26, except that methyl iodide was replaced by the correspondingalkylating agents.

Example 27

7-ethoxy-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c! 1!benzazepine

(a) 7-hydroxy-1-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine (300 mg, 0.856 mmole) obtained in Example 25 (e)was dissolved in a mixed solvent of acetone (10 ml) andN,N-dimethylformamide (10 ml). Potassium carbonate (142 mg, 1.027 mmole)and ethyl iodide (0.1 ml, 1.25 mmole) were added, and the mixture wassubjected to the same reaction and post-treatment as described inExample 26 to give7-ethoxy-1-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine (261 mg, 81%).

¹ H-NMR (DMSO-d₆): δ1.36 (3H, t), 3.71 (3H, s), 4.12 (2H, q), 6.01 (2H,s), 6.90 (2H, d), 6.91 (1H, dd), 7.05 (1H, d), 7.27 (2H, d), 8.15 (1H,d), 11.24 (1H, s).

EIMS: m/z 378 (M⁺ +1).

(b) 7-ethoxy-1-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine (a) (225 mg, 0.595 mmole) was subjected to deprotectionwith anisole (0.5 ml) and trifluoroacetic acid (6.0 ml) andpost-treatment in the same way as described in Example 26 to give thetitle compound, 7-ethoxy-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine as a pale yellow powder (159 mg, 100%).

¹ H-NMR (DMSO-d₆): δ1.37 (3H, t), 4.13 (2H, q), 6.93 (1H, d), 7.01 (1H,s), 8.25 (1H, d), 11.27 (1H, s).

EIMS: m/z 258 (M⁺ +1).

Example 28

7-allyloxy-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c! 1!benzazepine

(a) 7-hydroxy-1-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine (200 mg, 0.571 mmole) obtained in Example 25 (e)was dissolved in a mixed solvent of acetone (5 ml) andN,N-dimethylformamide (5 ml). Potassium carbonate (118 mg, 0.857 mmole)and allyl bromide (0.07 ml, 0.809 mmole) were added, and the mixture wassubjected to the same reaction and post-treatment as described inExample 26 to give7-allyloxy-1-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine (129 mg, 58%).

¹ H-NMR (DMSO-d₆): δ3.71 (3H, s), 4.67 (2H, d), 5.32 (1H, d), 5.44 (1H,dd), 6.01 (2H, s), 6.00-6.13 (1H, m), 6.90 (2H, d), 6.94 (1H, dd), 7.07(1H, d), 7.27 (2H, d), 8.16 (1H, d), 11.25 (1H, s).

EIMS: m/z 362 (M⁺ -N₂).

(b) 7-allyloxy-1-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine (a) (124 mg, 0.318 mmole) was subjected todeprotection with anisole (0.3 ml) and trifluoroacetic acid (3.0 ml) andpost-treatment in the same way as described in Example 26 to give thetitle compound, 7-allyloxy-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine as a pale yellow powder (74 mg, 86%).

¹ H-NMR (DMSO-d₆): δ4.67 (2H, d), 5.32 (1H, dd), 5.45 (1H, dd), 6.06(1H, ddd), 6.97 (1H, dd), 7.11 (1H, s), 8.26 (1H, d), 11.29 (1H, s).

EIMS: m/z 270 (M⁺).

Example 29

7-isopropoxy-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c! 1!benzazepine

(a) 7-hydroxy-1-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine (300 mg, 0.856 mmole) obtained in Example 25 (e)was dissolved in N,N-dimethylformamide (30 ml). Potassium carbonate (237mg, 1.71 mmole) and isopropyl bromide (1.60 ml, 17.0 mmole) were added,and the mixture was subjected to the same reaction and post-treatment asdescribed in Example 26 to give7-isopropoxy-1-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine (250 mg, 74%).

¹ H-NMR (DMSO-d₆): δ1.32 (6H, d), 3.71 (3H, s), 4.69 (1H, m), 6.01 (2H,s), 6.89 (2H, d), 6.90 (1H, dd), 7.03 (1H, d), 7.27 (2H, d), 8.14 (1H,d), 11.23 (1H, s).

SIMS: m/z 393 (M⁺ +1).

(b) 7-isopropoxy-1-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine (a) (268 mg, 0.683 mmole) was subjected todeprotection with anisole (0.5 ml) and trifluoroacetic acid (7.0 ml) andpost-treatment in the same way as described in Example 26 to give thetitle compound, 7-isopropoxy-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine as a pale yellow powder (175 mg, 94%).

¹ H-NMR (DMSO-d₆): δ1.33 (6H, d), 4.63-4.75 (1H, d), 6.92 (1H, dd), 7.07(1H, d), 8.24 (1H, d), 11.26 (1H, s).

EIMS: m/z 272 (M⁺).

Example 30

7-cyclohexylmethoxy-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine

(a) 7-hydroxy-1-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine (300 mg, 0,856 mmole) obtained in Example 25 (e)was dissolved in N,N-dimethylformamide (30 ml). Potassium carbonate (237mg, 1.71 mmole) and cyclohexylmethyl bromide (2.40 ml, 17.2 mmole) wereadded, and the mixture was subjected to the same reaction andpost-treatment as described in Example 26 to give7-cyclohexymethoxy-1-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine (292 mg, 76%).

¹ H-NMR (DMSO-d₆): δ0.97-1.32 (5H, m), 1.60-1.83 (6H, m), 3.70 (3H, s),3.85 (2H, d), 6.01 (2H, s), 6.79 (1H, d), 6.88 (2H, d), 6.93 (1H, s),7.26 (2H, d), 8.10 (1H, d), 11.20 (1H, brs).

SIMS: m/z 447 (M⁺ +1).

(b)7-cyclohexylmethoxy-1-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine (a) (292 mg, 0.654 mmole) was subjected todeprotection with anisole (0.5 ml) and trifluoroacetic acid (6.0 ml) andpost-treatment in the same way as described in Example 26 to give thetitle compound, 7-cyclohexylmethoxy-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine as a pale yellow powder (186 mg, 87%).

¹ H-NMR (DMSO-d₆): δ0.95-1.35 (5H, m), 1.60-1.90 (6H, m), 3.88 (2H, d),6.93 (1H, dd), 7.09 (1H, d), 8.25 (1H, d), 11.21 (1H, s).

EIMS: m/z 326 (M⁺).

Example 31

7-benzyloxy-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c! 1!benzazepine

(a) 7-hydroxy-1-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine (200 mg, 0.571 mmole) obtained in Example 25 (e)was dissolved in a mixed solvent of acetone (5 ml) andN,N-dimethylformamide (5 ml). Potassium carbonate (118 mg, 0.854 mmole)and benzyl bromide (0.10 ml, 0.841 mmole) were added, and the mixturewas subjected to the same reaction and post-treatment as described inExample 26 to give7-benzyloxy-1-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine (167 mg, 66%).

¹ H-NMR (DMSO-d₆): δ3.71 (3H, s), 5.20 (2H, s), 6.01 (2H, s), 6.89 (2H,d), 7.01 (2H, dd), 7.14 (1H, d), 7.27 (2H, d), 7.30-7.60 (5H, m), 8.16(1H, d), 11.28 (1H, s).

EIMS: m/z 440 (M⁺).

(b) To 7-benzyloxy-1-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine (a) (161 mg, 0.366 mmole) were added anisole (0.4ml) and trifluoroacetic acid (4.0 ml), and the mixture was stirred at60° C. for 30 minutes. After the reaction mixture was left standing forcooling, the solvent was removed under reduced pressure. Resultingcrystalline products were collected by filtration, and desiccated. A 1Naqueous sodium hydroxide solution was added, and the resultingcrystalline products were collected by filtration. To these crystallineproducts was added 1N hydrochloric acid, and the resulting crystallineproducts were collected by filtration, and desiccated to give the titlecompound, 7-benzyloxy-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine as a pale yellow powder (49 mg, 42%).

¹ H-NMR (DMSO-d₆): δ5.21 (2H, s), 7.04 (1H, dd), 7.18 (1H, d), 7.32-7.55(5H, m), 8.27 (1H, d), 11.29 (1H, s).

EIMS: m/z 326 (M⁺ +1).

Example 32

7-methoxycarbonylmethoxy-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine

(a) 7-hydroxy-1-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine (200 mg, 0.571 mmole) obtained in Example 25 (e)was dissolved in a mixed solvent of acetone (5 ml) andN,N-dimethylformamide (5 ml). Potassium carbonate (95 mg, 0.637 mmole)and methyl bromoacetate (0.08 ml, 0.845 mmole) were added, and themixture was subjected to the same procedures as described in Example 26to give1-(4-methoxybenzyl)-7-methoxycarbonylmethoxy-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine (178 mg, 74%).

¹ H-NMR (DMSO-d₆): δ3.71 (3H, s), 3.72 (3H, s), 4.92 (2H, s), 6.00 (2H,s), 6.89 (1H, d), 6.94 (1H, dd), 7.03 (1H, d), 7.27 (2H, d), 8.15 (1H,d), 11.25 (1H, s).

SIMS: m/z 423 (M⁺ +1).

(b)1-(4-methoxybenzyl)-7-methoxycarbonylmethoxy-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine (a) (166 mg, 0.393 mmole) was subjected todeprotection with anisole (0.5 ml) and trifluoroacetic acid (6.0 ml) andpost-treatment in the same way as described in Example 26 to give thetitle compound,7-methoxycarbonylmethoxy-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine as a pale yellow powder (102 mg, 86%).

¹ H-NMR (DMSO-d₆): δ3.73 (3H, s), 4.92 (2H, s), 6.97 (1H, dd), 7.07 (1H,d), 8.26 (1H, d), 11.29 (1H, s).

EIMS: m/z 303 (M⁺ +1).

Example 33

7-carboxymethoxy-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c! 1!benzazepine

(a) To1-(4-methoxybenzyl)-7-methoxycarbonylmethoxy-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine (215 mg, 0.509 mmole) obtained in Example 32 (e)was added a 1N aqueous sodium hydroxide solution (6 ml), and the mixturewas stirred at room temperature for 3.5 hours. The reaction mixture wasacidified with hydrochloric acid, and the resulting crystalline productswere collected by filtration, and desiccated to give7-carboxymethoxy-1-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine (192 mg, 92%).

¹ H-NMR (DMSO-d₆): δ3.71 (3H, s), 4.79 (2H, s), 6.01 (2H, s), 6.90 (2H,d), 6.91 (1H, dd), 7.05 (1H, d), 7.27 (2H, d), 8.15 (1H, d), 11.26 (1H,s), 13.30 (1H, brs).

SIMS: m/z 409 (M⁺ +1).

(b)7-carboxymethoxy-1-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine (182 mg, 0.446 mmole) obtained in the precedingstep (a) was subjected to deprotection with anisole (0.5 ml) andtrifluoroacetic acid (5.0 ml) and post-treatment in the same way asdescribed in Example 26 to give the title compound,7-carboxymethoxy-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c! 1!benzazepineas a pale yellow powder (126 mg, 98%).

¹ H-NMR (DMSO-d₆): δ4.80 (2H, s), 6.95 (1H, dd), 7.09 (1H, d), 8.27 (1H,d), 11.30 (1H, s), 13.20 (1H, brs).

SIMS: m/z 289 (M⁺ +1).

Example 34

7-acetonyloxy-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c! 1!benzazepine

(a) 7-hydroxy-1-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine (200 mg, 0.571 mmole) obtained in Example 25 (e)was dissolved in a mixed solvent of acetone (5 ml) andN,N-dimethylformamide (5 ml). Potassium carbonate (118 mg, 0.854 mmole)and bromoacetone (0.08 ml, 0.952 mmole) were added, and the mixture wassubjected to the same reaction and post-treatment as described inExample 26 to give7-acetonyloxy-1-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c!1!benzazepine (200 mg, 86%).

¹ H-NMR (DMSO-d₆): δ2.18 (3H, s), 3.71 (3H, s), 4.97 (2H, s), 6.01 (2H,s), 6.89 (2H, d), 6.90 (1H, dd), 6.95 (1H, d), 7.27 (2H, d), 8.14 (1H,d), 11.20 (1H, s).

SIMS: m/z 407 (M⁺ +1).

(b)1-(4-methoxybenzyl)-7-methoxycarbonylmethoxy-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine (a) (166 mg, 0.393 mmole) was subjected todeprotection with anisole (0.5 ml) and trifluoroacetic acid (6.0 ml) andpost-treatment in the same way as described in Example 26 to give thetitle compound,7-methoxycarbonylmethoxy-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine as a pale yellow powder (102 mg, 86%).

¹ H-NMR (DMSO-d₆): δ3.73 (3H, s), 4.92 (2H, s), 6.97 (1H, dd), 7.07 (1H,d), 8.26 (1H, d), 11.29 (1H, s).

EIMS: m/z 303 (M⁺ +1).

(b) 7-acetonyloxy-1-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c!1!benzazepine (229 mg, 0.563 mmole) obtained in the preceding step(a) was subjected to deprotection with anisole (0.5 ml) andtrifluoroacetic acid (6.0 ml) and post-treatment in the same way asdescribed in Example 26 to give the title compound,7-acetonyloxy-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c! 1!benzazepine as apale yellow powder (149 mg, 92%).

¹ H-NMR (DMSO-d₆): δ2.19 (3H, s), 4.98 (2H, s), 6.93 (1H, dd), 6.98 (1H,d), 8.25 (1H, d), 11.25 (1H, s).

SIMS: m/z 287 (M⁺ +1).

Example 35

7-cyanomethoxy-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c! 1!benzazepine

(a) 7-hydroxy-1-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine (300 mg, 0.856 mmole) obtained in Example 25 (e)was dissolved in a mixed solvent of acetone (5 ml) andN,N-dimethylformamide (5 ml). Potassium carbonate (142 mg, 1.027 mmole)and bromoacetonitrile (0.09 ml, 1.29 mmole) were added, and the mixturewas subjected to the same reaction and post-treatment as described inExample 26 to give7-cyanomethoxy-1-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine (231 mg, 69%).

¹ H-NMR (DMSO-d₆): δ3.71 (3H, s), 5.27 (2H, s), 6.00 (2H, s), 6.90 (2H,d), 7.06 (1H, dd), 7.16 (1H, d), 7.28 (2H, d), 8.22 (1H, d), 11.36 (1H,s).

EIMS: m/z 361 (M⁺ -N₂).

(b) 7-cyanomethoxy-1-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine (a) (172 mg, 0.424 mmole) were added anisole (0.4ml) and trifluoroacetic acid (4.0 ml), and the mixture was stirred at60° C. for 15 minutes. After the reaction mixture was left standing forcooling, the solvent was removed under reduced pressure. Resultingcrystalline products were collected by filtration, and desiccated togive the title compound, 7-cyanomethoxy-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine as a pale yellow powder (105 mg, 92%).

¹ H-NMR (DMSO-d₆): δ5.27 (2H, s), 7.09 (1H, dd), 7.21 (1H, d), 8.35 (1H,d), 11.39 (1H, s).

EIMS: m/z 269 (M⁺).

Example 36

7-carbamoylmethoxy-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c! 1!benzazepine

Anisole (0.4 ml) and trifluoroacetic acid (4.0 ml) were added to7-cyanomethoxy-1-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine obtained in Example 35 (a), and the mixture wasstirred at 60° C. for 3 days. After the reaction mixture was leftstanding for cooling, the solvent was removed under reduced pressure.Resulting precipitates were collected by filtration, and desiccated togive the title compound,7-carbamoylmethoxy-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c! 1!benzazepineas a pale yellow powder (67 mg, 56%).

¹ H-NMR (DMSO-d₆): δ4.56 (2H, s), 6.95 (1H, dd), 7.10 (1H, d), 7.43 (1H,d), 7.61 (1H, s), 8.27 (1H, d), 11.34 (1H, s).

SIMS: m/z 288 (M⁺ +1).

Example 37

7-(4-methoxyphenacyloxy)-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine

(a) 7-hydroxy-1-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine (200 mg, 0.571 mmole) obtained in Example 25 (e)was dissolved in N,N-dimethylformamide (10 ml). Potassium carbonate (95mg, 0.687 mmole) and 4-methoxyphenacyl bromide (196 mg, 0.856 mmole)were added, and the mixture was subjected to the same reaction andpost-treatment as described in Example 26 to give1-(4-methoxybenzyl)-7-(4-methoxyphenacyloxy)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine (236 mg, 83%).

¹ H-NMR (DMSO-d₆): δ3.71 (3H, s), 3.87 (3H, s), 5.68 (2H, s), 6.01 (2H,s), 6.90 (2H, d), 6.96 (1H, dd), 7.03 (1H, d), 7.11 (2H, d), 7.27 (2H,d), 8.00 (2H, d), 8.15 (1H, d), 11.19 (1H, s).

SIMS: m/z 499 (M⁺ +1).

(b)1-(4-methoxybenzyl)-7-(4-methoxyphenacyloxy)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine (285 mg, 0.572 mmole) was subjected to deprotectionwith anisole (0.5 ml) and trifluoroacetic acid (6.0 ml) andpost-treatment in the same way as described in Example 26 to give7-(4-methoxyphenacyloxy)-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine (203 mg, 94%).

¹ H-NMR (DMSO-d₆): δ3.87 (3H, s), 5.68 (2H, s), 6.99 (1H, dd), 7.07 (1H,d), 7.12 (2H, d), 8.01 (2H, d), 8.26 (1H, d), 11.22 (1H, s).

SIMS: m/z 379 (M⁺ +1).

Example 38

7-(2-methoxyethoxy)-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine

(a) 7-hydroxy-1-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine (300 mg, 0.856 mmole) obtained in Example 25 (e)was dissolved in N,N-dimethylformamide (10 ml). Potassium carbonate (237mg, 1.715 mmole) and (2-chloroethyl)-methyl ether (1.56 ml, 17.1 mmole)were added, and the mixture was subjected to the same reaction andpost-treatment as described in Example 26 to give1-(4-methoxybenzyl)-7-(2-methoxyethoxy)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine (96 mg, 27%).

¹ H-NMR (DMSO-d₆): δ3.31 (3H, s), 3.71 (3H, s), 3.69 (2H, t), 4.19 (2H,t), 6.01 (2H, s), 6.90 (2H, d), 6.95 (1H, dd), 7.05 (1H, d), 7.27 (2H,d), 8.16 (1H, d), 11.24 (1H, s).

SIMS: m/z 409 (M⁺ +1).

(b)1-(4-methoxybenzyl)-7-(2-methoxyethoxy)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine (90 mg, 0.220 mmole) obtained in the preceding step(a) was subjected to deprotection with anisole (0.1 ml) andtrifluoroacetic acid (2.0 ml) and post-treatment in the same way asdescribed in Example 26 to give7-(2-methoxyethoxy)-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine (52 mg, 81%).

¹ H-NMR (DMSO-d₆): δ3.32 (3H, s), 3.70 (2H, t), 4.19 (2H, t), 6.98 (1H,dd), 7.10 (1H, d), 8.27 (1H, d), 11.27 (1H, brs).

SIMS: m/z 289 (M⁺ +1).

The compounds described in Example 39 was synthesized in the same manneras described in Example 8, except that5-(4-methoxybenzyloxy)-2-nitrobenzaldehyde was replaced by5-methoxymethoxy-2-nitrobenzaldehyde.

Example 39

8-hydroxy-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c! 1!benzazepine

(a) 1.5N butyllithium (14.9 ml, 22.4 mmole) was added under the argonatmosphere to a solution of diisopropylamine (3.3 ml, 23.8 mmole) intetrahydrofuran (40 ml) at -78° C., and the mixture was stirred for 1.5hours. Next, a solution of ethyl propiolate (2.7 ml, 26.8 mmole) intetrahydrofuran (10 ml) and a solution of5-methoxymethoxy-2-nitrobenzaldehyde (3.15 g, 14.9 mmole) intetrahydrofuran (10 ml) were added in this sequence, and the reactionmixture was stirred at -78° C. for further 1 hour. After a solution ofacetic acid (2.6 ml, 46.2 mmole) in tetrahydrofuran (10 ml) was added,the reaction mixture was extracted with ethyl acetate. The organic layerwas washed with dilute hydrochloric acid, a saturated aqueous sodiumhydrogen carbonate solution and a saturated aqueous saline in thissequence. After the organic layer was dried over anhydrous magnesiumsulfate, the solvent was removed under reduced pressure to give ethyl4-hydroxy-4(5-methoxymethoxy-2-nitrophenyl)-2-butynoate as an oil (6.26g).

Ethyl 4-hydroxy-4(5-methoxymethoxy-2-nitrophenyl)-2-butynoate thusobtained was dissolved in toluene (25 ml), 4-methoxybenzylazide (7.29 g,44.7 mmole) was added, and the mixture was stirred under heating at 100°C. for 3.5 hours. After the reaction mixture was cooled to roomtemperature, the toluene was removed under reduced pressure. The residuewas purified by silica gel column chromatography (hexane:ethylacetate=2:1) to give a 1:1 mixture of ethyl4(hydroxy-(5-methoxymethoxy-2-nitrophenyl)methyl)-1-(4-methoxybenzyl)-1,2,3-triazole-5-carboxylate(a-1: low polar product (LP)), and ethyl5-(hydroxy-(5-methoxymethoxy-2-nitrophenyl)methyl)-1-(4-methoxybenzyl)-1,2,3-triazole-4-carboxylate(a-2: highly polar product (MP)) as a brown oil (3.75 g, 53%).

Mixture of a-1 (LP) and a-2 (MP):

¹ H-NMR (CDCl₃): δ1.37 (3/2H, t), 1.39 (3/2H, t), 3.39 (3/2H, s), 3.49(3/2H, s), 3.69 (3/2H, s), 3.78 (3/2H, s), 4.41 (1H, q), 4.42 (1H, q),5.01 (1H, d), 5.27 (1H, d), 5.36 (1/2H, d), 5.50 (1H, d), 5.72 (1H, d),5.81 (1/2H, d), 6.20 (1/2H, d), 6.63 (1H, d), 6.84 (1H, d), 6.95 (1/2H,dd), 7.05 (1H, d), 7.09 (1/2H, dd), 7.21 (1H, d), 7.61 (1/2H, d), 7.92(1/2H, d), 8.15 (1/2H, d).

EIMS: m/z 472 (M⁺ +1).

(b) Manganese dioxide (11.25 g) was added in two portions to a solutionof the 1:1 mixture (3.75 g, 7.94 mmole) of the compounds a-1 and a-2 inmethylene chloride (80 ml), and the mixture was stirred at roomtemperature for 20 hours. After the reaction mixture was filteredthrough celite and washed with methylene chloride, the solvent wasremoved under reduced pressure. The residue thus obtained was purifiedby silica gel column chromatography (toluene: diethyl ether=2:1) to giveethyl1-(4-methoxybenzyl)-4(5-methoxymethoxy-2-nitrobenzoyl)-1,2,3-triazole-5-carboxylate(b-1: LP) as a colorless crystalline powder (1.01 g, 27.1%), and ethyl1-(4-methoxybenzyl)-5-(5-methoxymethoxy-2-nitrobenzoyl)-1,2,3-triazole-4-carboxylate(b-2: MP) as a colorless crystalline powder (1.30 g, 34.9%).

b-1 (LP);

¹ H-NMR (CDCl₃): δ1.37 (3H, t), 3.48 (3H, s), 3.79 (3H, s), 4.43 (2H,q), 5.27 (2H, s), 5.72 (2H, s), 6.86 (2H, d), 7.15 (2H, d), 7.22-7.25(3H, m), 8.19 (1H, d).

EIMS: m/z 470 (M⁺).

b-2 (MP);

¹ H-NMR (CDCl₃): δ1.16 (3H, t), 3.47 (3H, s), 3.79 (3H, s), 4.06 (2H,q), 5.23 (2H, s), 5.84 (2H, s), 6.88 (2H, d), 6.91 (1H, d), 7.24 (1H,dd), 7.40 (2H, d), 8.08 (1H, d).

EIMS: m/z 470 (M⁺).

(c) A 1N aqueous sodium hydroxide solution (4.8 ml) was added to asolution of ethyl1-(4-methoxybenzyl)-4(5-methoxymethoxy-2-nitrobenzoyl)-1,2,3-triazole-5-carboxylate(b-1) (1.13 g, 2.40 mmole) obtained in the preceding step (b) intetrahydrofuran (25 ml), and the mixture was stirred at room temperaturefor 2 hours. After the reaction mixture was acidified with hydrochloricacid, it was extracted with ethyl acetate, and washed with a saturatedaqueous saline.

After the organic layer was dried over anhydrous magnesium sulfate, thesolvent was removed under reduced pressure to give1-(4-methoxybenzyl)-4(5-methoxymethoxy-2-nitrobenzoyl)-1,2,3-triazole-5-carboxylicacid (c-1': LP) (1.06 g). The product was then dissolved in a mixture ofethanol:ethyl acetate=1:1 (100 ml), 10% palladium on carbon (100 mg) wasadded, and the mixture was stirred under the hydrogen atmosphere at roomtemperature for 23 hours. The reaction mixture filtered through celite,and the filtrate was concentrated under reduced pressure. Precipitateswere collected by filtration to give4(2-amino-5-methoxymethoxybenzoyl)-1-(4-methoxybenzyl)-1,2,3-triazole-5-carboxylicacid (c-1: LP) as a yellow crystalline powder (956.4 mg, 99% ).

c-1 (LP);

¹ H-NMR (CDCl₃): δ3.49 (3H, s), 3.78 (3H, s), 5.13 (2H, s), 6.05 (2H,s), 6.69 (1H, d), 6.86 (2H, d), 7.22 (1H, dd), 7.44 (2H, d), 8.45 (1H,d).

FDMS: m/z 412 (M⁺).

c-1' (LP);

¹ H-NMR (CDCl₃): δ3.49 (3H, s), 3.78 (3H, s), 5.28 (2H, s), 6.03 (2H,s), 6.85 (2H, dt), 7.13 (1H, d), 7.33 (1H, dd), 7.41 (2H, dt), 8.27 (1H,d).

SIMS: m/z 443 (M⁺ +1).

In the same manner as above, a solution of ethyl1-(4-methoxybenzyl)-5-(5-methoxymethoxy-2-nitrobenzoyl)-1,2,3-triazole-4-carboxylate(b-2) (1.23 g, 2.62 mmole) in tetrahydrofuran (25 ml) was hydrolyzedwith a 1N aqueous sodium hydroxide solution (5.2 ml) at room temperaturefor 5 hours to give1-(4-methoxybenzyl)-5-(5-methoxymethoxy-2-nitrobenzoyl)-1,2,3-triazole-4-carboxylicacid (c-2': MP) (1.08 g, 93%)

Furthermore, the product dissolved in a mixture of ethanol:ethylacetate=2:1 (75 ml) was reduced in the presence of 10% palladium oncarbon (100 mg) under the hydrogen atmosphere at room temperature for 29hours to give5-(2-amino-5-methoxymethoxybenzoyl)-1-(4-methoxybenzyl)-1,2,3-triazole-4-carboxylicacid (c-2: MP) (974 mg, 100.0%).

c-2' (MP);

¹ H-NMR (CDCl₃): δ3.47 (3H, s), 3.81 (3H, s), 5.24 (2H, s), 5.84 (2H,s), 6.91 (2H, d), 7.02 (1H, d), 7.24 (1H, dd), 7.46 (2H, d), 8.09 (1H,d).

SIMS: m/z 443 (M⁺ +1).

c-2 (MP);

¹ H-NMR (CDCl₃): δ3.32 (3H, s), 3.68 (3H, s), 4.79 (2H, s), 5.46 (2H,s), 6.34 (2H, d), 7.04 (1H, dd), 7.06 (2H, d).

SIMS: m/z 413 (M⁺ +1).

(d) Under the argon atmosphere, to a solution of4(2-amino-5-methoxymethoxybenzoyl)-1-(4-methoxybenzyl)-1,2,3-triazole-5-carboxylicacid (c-1) (647 mg, 1.57 mmole) in methylene chloride (15 ml) were addedunder ice-cooling tributylamine (0.39 ml, 1.65 mmole),2-chloro-1-methylpyridinium p-toluenesulfonate (519 mg, 1.73 mmole) and3,4-dihydro-2H-pyrido 1,2-a!pyrimidin-2-one (279 mg, 1.88 mmole) in thissequence, and the mixture was stirred for 1 hour and at room temperaturefor 17 hours. Resulting precipitates were collected by filtration,pulverized with diethyl ether, and desiccated to give

3-(4-methoxybenzyl)-8-methoxymethoxy-4(5H),10-dioxo-3H-1,2,3-triazolo5.4-c! 1!benzazepine (d-1: LP) as a yellow crystalline powder (394.6 mg,64%).

d-1 (LP);

¹ H-NMR (DMSO-d₆): δ3.39 (3H, s), 3.72 (3H, s), 5.26 (2H, s), 6.08 (2H,s), 6.90 (2H, d), 7.30 (2H, d), 7.42 (1H, dd), 7.50 (1H, d), 7.80 (1H,d), 11.45 (1H, s).

SIMS: m/z 395 (M⁺ +1).

In the same manner as above, starting from5-(2-amino-5-methoxymethoxybenzoyl)-1-(4-methoxybenzyl)-1,2,3-triazole-4-carboxylicacid (c-2) (850 mg, 2.06 mmole),1-(4-methoxybenzyl)-8-methoxymethoxy-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine (d-2: MP) as a yellow crystalline powder (577.3 mg,71%).

d-2 (MP);

¹ H-NMR (DMSO-d₆): δ3.39 (3H, s), 3.72 (3H, s), 5.24 (2H, s), 5.99 (2H,s), 6.91 (2H, d), 7.29 (2H, d), 7.44 (2H, dd), 7.51 (1H, d), 7.75 (1H,d), 11.30 (1H, s).

SIMS: m/z 395 (M⁺ +1).

(e) To3-(4-methoxybenzyl)-8-methoxymethoxy-4(5H),10-dioxo-3H-1,2,3-triazolo5.4-c! 1!benzazepine (d-1) (200 mg, 0.51 mmole) were added anisole (1.5ml) and trifluoroacetic acid (15 ml), and the mixture was stirred atroom temperature for 3 hours. The solvent was removed under reducedpressure. The residue was washed and desiccated to give the titlecompound, 8-hydroxy-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine (e) as a yellow powder (110 mg, 90%), which was the samecompound as the title compound of Example 8.

(f)1-(4-methoxybenzyl)-8-methoxymethoxy-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine (d-2) obtained in the preceding step (d) (43 mg,0.11 mmole) was dissolved in dichloromethane (2 ml), trifluoroaceticacid (40 μl, 0.55 mmole) was added, and the mixture was stirred at roomtemperature for 23 hours. The solvent was then removed under reducedpressure. The residue thus obtained was washed and desiccated to give8-hydroxy-1-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine (38.7 mg, 99%).

¹ H-NMR (DMSO-d₆): δ3.71 (3H, s), 6.08 (2H, s), 6.90 (2H, s), 7.18 (1H,dd), 7.27 (2H, d), 7.41 (1H, dd), 7.51 (1H, d), 9.89 (1H, s), 11.20 (1H,s).

EIMS: m/z 351 (M⁺ +1).

Anisole (0.2 ml) and trifluoroacetic acid (2 ml) were added to thiscompound (24.1 mg) for deprotection at 60° C. to give the titlecompound, 8-hydroxy-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine which was the same as obtained in the preceding step (e),as a white powder (15.8 mg, 100%).

Example 40

8-ethoxy-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c! 1!benzazepine

(a) 8-hydroxy-1-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine (200 mg, 0.58 mmole) obtained in Example 39 (f) wasdissolved in a mixed solvent of N,N-dimethylformamide (4 ml) and acetone(2 ml). Potassium carbonate (158 mg, 1.14 mmole) and ethyl iodide (92μl, 1.14 mmole) were added, and the mixture was stirred at roomtemperature for 23 hours. The reaction mixture was diluted with water(20 ml), and crystalline products were collected by filtration andpulverized with diethyl ether to give8-ethoxy-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine as a yellow crystalline powder (113.7 mg, 3%).

¹ H-NMR (DMSO-d₆): δ1.34 (3H, t), 3.71 (3H, s), 4.06 (2H, q), 6.01 (2H,s), 6.89 (2H, d), 7.26 (2H, d), 7.28 (1H, dd), 7.38 (1H, d), 7.53 (1H,d).

SIMS: m/z 379 (M⁺ +1).

(b) To 8-ethoxy-1-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine (131.5 mg, 0.35 mmole) were added anisole (0.4 ml)and trifluoroacetic acid (4 ml), and the mixture was stirred at 60° C.for 3 hours. The solvent was then removed under reduced pressure. Theresidues thus obtained was washed and desiccated to give the titlecompound, 8-ethoxy-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c! 1!benzazepineas a yellow powder (62.3 mg, 69%).

¹ H-NMR (DMSO-d₆): δ1.36 (3H, t), 4.11 (2H, q), 7.38 (1H, dd), 7.53 (1H,d), 7.70 (1H, d), 11.37 (1H, brs).

SIMS: m/z 259 (M⁺ +1).

The compounds in the following Examples 41 and 42 were synthesized withthe corresponding alkylating agents.

Example 41

8-methoxy-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c! 1!benzazepine

(a) Starting from8-hydroxy-1-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine (200 mg, 0.58 mmole) obtained in Example 39 (f) wasobtained 8-methoxy-1-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine as a yellow crystalline powder (97 mg, 46%) in thesame manner as in Example 40, except that ethyl iodide was replaced bymethyl iodide.

¹ H-NMR (DMSO-d₆): δ3.72 (3H, s), 3.83 (3H, s), 6.00 (2H, s), 6.91 (2H,d), 7.29 (2H, d), 7.40 (1H, dd), 7.51 (1H, d), 7.59 (1H, d), 11.30 (1H,s).

EIMS: m/z 364 (M⁺).

(b) To 1-(4-methoxybenzyl)-8-methoxy-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine was deprotected in the same manner as in Example 40(b) to give the title compound,8-methoxy-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c! 1!benzazepine as ayellow powder (46 mg, 71%).

¹ H-NMR (DMSO-d₆): δ3.84 (3H, s), 7.39 (1H, dd), 7.54 (1H, d), 7.72 (1H,d), 11.38 (1H, s).

EIMS: m/z 244 (M⁺).

Example 42

8-methoxycarbonylmethoxy-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine

(a) 8-hydroxy-1-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine (200 mg, 0.58 mmole) obtained in Example 39 (f) wasdissolved in a mixed solvent of N,N-dimethylformamide (3 ml) and acetone(3 ml). Potassium carbonate (136 mg, 0.98 mmole) and methyl bromoacetate(84 μl, 0.88 mmole) were added, and the mixture was stirred at roomtemperature for 22 hours. The reaction mixture was diluted with water(20 ml), and crystalline products were collected by filtration andpulverized with diethyl ether to give1-(4-methoxybenzyl)-8-methoxycarbonylmethoxy-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine as a yellow crystalline powder (181.6 mg, 75%).

¹ H-NMR (DMSO-d₆): δ3.70 (3H, s), 3.71 (3H, s), 4.89 (2H, s), 6.00 (2H,s), 6.90 (2H, d), 7.28 (2H, d), 7.44 (1H, dd), 7.51 (1H, d), 7.56 (1H,d), 11.32 (1H, brs).

FDMS: m/z 423 (M⁺ +1).

(b) To1-(4-methoxybenzyl)-8-methoxycarbonylmethoxy-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine (251.2 mg, 0.6 mmole) were added anisole (0.6 ml)and trifluoroacetic acid (6 ml), and the mixture was stirred at 60° C.for 3 hours. The solvent was then removed under reduced pressure. Theresidues thus obtained was washed and desiccated to give the titlecompound, 8-methoxycarbonylmethoxy-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine as a yellow powder (180.1 mg, 100%).

¹ H-NMR (DMSO-d₆): δ3.75 (3H, s), 4.91 (2H, s), 7.43 (1H, dd), 7.54 (1H,d), 7.68 (1H, d), 11.40 (1H, brs).

FDMS: m/z 302 (M⁺ +1).

Example 43

7,8-dimethoxy-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c! 1!benzazepine

(a) 1.5N butyllithium (26.8 ml, 40.2 mmole) was added under the argonatmosphere to a solution of diisopropylamine (6.0 ml, 42.8 mmole) intetrahydrofuran (75 ml) at -78° C., and the mixture was stirred for 1hour. Next, ethyl propiolate (3.4 ml, 33.5 mmole) and a solution of4,5-dimethoxy-2-nitrobenzaldehyde (5.0 g, 23.7 mmole) in tetrahydrofuran(50 ml) were added in this sequence, and the reaction mixture wasstirred at -78° C. for further 1.5 hours. After a solution of aceticacid (7.0 ml, 122 mmole) in tetrahydrofuran (20 ml) followed by waterwere added, the reaction mixture was extracted with ethyl acetate. Theorganic layer was washed with dilute hydrochloric acid, water, asaturated aqueous sodium hydrogen carbonate solution and a saturatedaqueous saline in this sequence. After the organic layer was dried overanhydrous magnesium sulfate, the solvent was removed under reducedpressure to give ethyl4-hydroxy-4(4,5-dimethoxy-2-nitrophenyl)-2-butynoate as an oil (8.59 g).Ethyl 4-hydroxy-4(4,5-dimethoxy-2-nitrophenyl)-2-butynoate thus obtainedwas dissolved in toluene (80 ml), 4-methoxybenzylazide (11.6 g, 71.1mmole) was added, and the mixture was stirred under heating at 100° C.overnight. After the reaction mixture was cooled to room temperature, itwas purified by silica gel column chromatography (hexane:ethylacetate=2:1).

The resulting precipitates in the eluates were collected by filtrationto give a 1:5 mixture of ethyl4-(hydroxy-(4,5-dimethoxy-2-nitrophenyl)methyl)-1-(4-methoxybenzyl)-1,2,3-triazole-5-carboxylate(a-1: low polar product (LP)), and ethyl5-(hydroxy-(4,5-dimethoxy-2-nitrophenyl)methyl)-1-(4-methoxybenzyl)-1,2,3-triazole-4-carboxylate(a-2: highly polar product (MP)) (2.60 g, 23%). In addition,concentration of the filtrate gave a 2.5:1 mixture of the compound (a-1:(LP)) and the compound (a-2: (MP)) (4.68 g, 42% ). The 2.5:1 mixture ofa-1 (LP) and a-2 (MP):

¹ H-NMR (CDCl₃): δ1.38 (15/7H, t), 1.39 (6/7H, t), 3.56 (6/7H, s), 3.72(6/7H, s), 3.78 (15/7H, s), 3.91 (6/7H, s), 3.97 (15/7H, s), 3.99(15/7H, s), 4.41 (4/7H, q), 4.44 (10/7H, q), 4.97 (5/7H, d), 5.07 (2/7H,d), 5.48 (2/7H, d), 5.78 (5/7H, d), 5.71 (2/7H, d), 5.84 (5/7H, d), 6.32(2/7H, s), 6.83 (10/7H, d), 6.67 (4/7H, d), 6.99 (4/7H, d), 7.07 (2/7H,d), 7.21 (10/7H, d), 7.48 (2/7H, s), 7.51 (5/7H, s), 7.71 (5/7H, s).

EIMS: m/z 472 (M⁺).

(b) Manganese dioxide (14 g) was added to a solution of the 2.5:1mixture (4.63 g, 9.80 mmole) of the compounds a-1 and a-2 obtained inthe preceding step (a) in methylene chloride (100 ml), and the mixturewas stirred at room temperature overnight. Manganese dioxide (4.6 g) wasfurther added, and the mixture was stirred at room temperature for 8hours. After the reaction mixture was filtered through celite and washedwith ethyl acetate, the solvent was removed under reduced pressure. Theresidue thus obtained was purified by silica gel column chromatography(hexane:ethyl acetate=2:1) to give ethyl1-(4-methoxybenzyl)-4(4,5-dimethoxy-2-nitrobenzoyl)-1,2,3-triazole-5-carboxylate(b-1: LP) as a brown crystalline powder (2.75 g, 60%), and ethyl1-(4-methoxybenzyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)-1,2,3-triazole-4-carboxylate(b-2: MP) as a brown crystalline powder (1.12 g, 24%).

b-1 (LP);

¹ H-NMR (CDCl₃): δ1.38 (3H, t), 3.78 (3H, s), 3.98 (3H, s), 4.02 (3H,s), 4.43 (2H, q), 5.72 (2H, s), 6.85 (2H, d), 6.99 (1H, s), 7.24 (2H,d), 7.69 (1H, d).

SIMS: m/z 471 (M⁺ +1).

b-2 (MP);

¹ H-NMR (CDCl₃): δ1.19 (3H, t), 3.79 (3H, s), 3.91 (3H, s), 4.00 (3H,s), 4.10 (2H, q), 5.79 (2H, s), 6.80 (1H, d), 6.88 (2H, d), 7.42 (2H,d), 7.52 (1H, s).

EIMS: m/z 470 (M⁺).

(c) A 1N aqueous sodium hydroxide solution (13 ml) was added to asolution of ethyl1-(4-methoxybenzyl)-4(4,5-dimethoxy-2-nitrobenzoyl)-1,2,3-triazole-5-carboxylate(b-1) (3.04 g, 6.46 mmole) obtained in the preceding step (b) intetrahydrofuran (40 ml), and the mixture was stirred at room temperaturefor 3.5 hours. The reaction mixture was diluted with ether, and waterwas added. After the aqueous layer was acidified with hydrochloric acid,it was extracted with ethyl acetate, and washed with water and asaturated aqueous saline.

After the organic layer was dried over anhydrous magnesium sulfate, thesolvent was removed under reduced pressure to give1-(4-methoxybenzyl)-4(4,5-dimethoxy-2-nitrobenzoyl)-1,2,3-triazole-5-carboxylicacid (c-1': LP) (2.55 g, 89%). The product was then dissolved in amixture of ethanol (50 ml) and ethyl acetate (50 ml), 10% palladium oncarbon (129 mg) was added, and the mixture was stirred under thehydrogen atmosphere at room temperature for 4 hours. After methylenechloride was added to the reaction mixture to dissolve the crystallineproducts, the mixture was filtered through celite, and the filtrate wasconcentrated under reduced pressure to give4(2-amino-4,5-dimethoxybenzoyl)-1-(4-methoxybenzyl)-1,2,3-triazole-5-carboxylicacid (c-1: LP) (1.06 g, 100%).

c-1' (LP);

¹ H-NMR (CDCl₃): δ3.78 (3H, s), 3.99 (3H, s), 4.06 (3H, s), 6.02 (2H,s), 6.84 (2H, d), 6.94 (1H, s), 7.40 (2H, d), 7.76 (1H, s), 13.80 (1H,brs).

SIMS: m/z 443 (M⁺ +1).

c-1 (LP);

¹ H-NMR (CDCl₃): δ3.78 (3H, s), 3.88 (3H, s), 3.94 (3H, s), 6.06 (2H,s), 6.11 (1H, s), 6.86 (2H, d), 7.45 (2H, d), 8.58 (1H, s).

SIMS: m/z 413 (M⁺ +1).

In the same manner as above, a solution of ethyl1-(4-methoxybenzyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)-1,2,3-triazole-4-carboxylate(b-2) (3.12 g, 6.63 mmole) in tetrahydrofuran (100 ml) was hydrolyzedwith a 1N aqueous sodium hydroxide solution (13 ml) at room temperaturefor 3.5 hours to give1-(4-methoxybenzyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)-1,2,3-triazole-4-carboxylicacid (c-2': MP) (2.32 g, 79%)

c-2' (MP);

¹ H-NMR (CDCl₃): δ3.80 (3H, s), 3.94 (3H, s), 4.00 (3H, s), 5.79 (2H,s), 6.89 (1H, s), 6.91 (2H, d), 7.47 (2H, d), 7.54 (1H, s).

SIMS: m/z 443 (M⁺ +1).

(d) Under the argon atmosphere, to a solution of4(2-amino-4,5-dimethoxybenzoyl)-1-(4-methoxybenzyl)-1,2,3-triazole-5-carboxylicacid (c-1) (1.05 g, 2.55 mmole) in methylene chloride (30 ml) were addedunder ice-cooling tributylamine (0.64 ml, 2.69 mmole),2-fluoro-1-methylpyridinium p-toluenesulfonate (793 mg, 2.80 mmole) and3,4-dihydro-2H-pyrido 1,2-a!pyrimidin-2-one (453 mg, 3.06 mmole) in thissequence, and the mixture was stirred under ice-cooling for 1 hour andat room temperature for further 2 hours.

The reaction mixture was diluted with water and extracted withchloroform. The organic layer was washed with dilute hydrochloric acid,water, a saturated aqueous sodium hydrogen carbonate solution, and asaturated aqueous saline, dried over anhydrous magnesium sulfate, andthe solvent was concentrated under reduced pressure. Resultingprecipitates were collected by filtration, washed with diethyl etherfollowed by water, and desiccated to give7,8-dimethoxy-3-(4-methoxybenzyl)-4(5H),10-dioxo-3H-1,2,3-triazolo5,4-c!1!benzazepine (d-1: LP) as a pale yellow crystalline powder (477mg, 48%).

d-1 (LP);

¹ H-NMR (DMSO-d₆): δ3.72 (3H, s), 3.84 (6H, s), 6.09 (2H, s), 6.90 (2H,d), 7.16 (1H, s), 7.30 (2H, d), 7.67 (1H, s), 11.33 (1H, s).

EIMS: m/z 394 (M⁺).

(e) To7,8-dimethoxy-3-(4-methoxybenzyl)-4(5H),10-dioxo-3H-1,2,3-triazolo5,4-c!1!benzazepine (d-1) (471 mg, 1.19 mmole) were added anisole (0.5ml) and trifluoroacetic acid (5.0 ml), and the mixture was stirred at60° C. for 3 hours. The solvent was then removed under reduced pressure.The resulting precipitates were collected by filtration, washed withdiethyl ether followed by water and desiccated to give the titlecompound, 7,8-dimethoxy-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine (eH) as a yellow powder (319 mg, 98%). The product,7,8-dimethoxy-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c! 1!benzazepine (e)(238 mg, 0.867 mmole) was dissolved in a 1N aqueous sodium hydroxidesolution, and purified with DIAION HP-20 (water:acetone=9:1) to give7,8-dimethoxy-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c! 1!benzazepine (e')(231 mg, 90%). (e);

¹ H-NMR (DMSO-d₆): δ3.85 (3H, s), 3.86 (3H, s), 7.22 (1H, s), 7.70 (1H,s), 11.23 (1H, s).

SIMS: m/z 275 (M⁺ +1). (e');

FDMS: m/z 274 (M⁺ -Na+1).

Example 44

7,8-dimethyl-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c! 1!benzazepine

(a) 1.5N butyllithium (15.8 ml, 24.88 mmole) was added under the argonatmosphere to a solution of diisopropylamine (3.66 ml, 26.1 mmole) intetrahydrofuran (50 ml) at -78° C., and the mixture was stirred for 30minutes. To the reaction mixture were next added a solution of ethylpropiolate (2.20 ml, 21.71 mmole) in tetrahydrofuran (10 ml) and asolution of 4,5-dimethyl-2-nitrobenzaldehyde (2.60 g, 14.51 mmole) intetrahydrofuran (20 ml) in this sequence, and the reaction mixture wasstirred at -78° C. for further 1.5 hours. After a solution of aceticacid (3.2 ml, 53.3 mmole) in tetrahydrofuran (10 ml) followed by waterwere added, the reaction mixture was extracted with ethyl acetate (300ml). The organic layer was washed with dilute hydrochloric acid, water,a saturated aqueous sodium hydrogen carbonate solution and a saturatedaqueous saline in this sequence. After the organic layer was dried overanhydrous magnesium sulfate, the solvent was removed under reducedpressure to give ethyl4-hydroxy-4(4,5-dimethyl-2-nitrophenyl)-2-butynoate as an oil (4.363 g).

¹ H-NMR (CDCl₃): δ1.31 (3H, t), 2.35 (3H, s), 2.38 (3H, s), 3.35 (1H,d), 4.24 (2H, q), 6.09 (1H, d), 7.61 (1H, s), 7.88 (1m, s).

FDMS: m/z 278 (M⁺ +1).

Ethyl 4-hydroxy-4(4,5-dimethyl-2-nitrophenyl)-2-butynoate (4.363 g) thusobtained was dissolved in toluene (60 ml), 4-methoxybenzylazide (7.48 g,43.55 mmole) was added, and the mixture was stirred under heating at100° C. for 10 hours. After the reaction mixture was cooled to roomtemperature, it was concentrated under reduced pressure. The residueobtained was purified by silica gel column chromatography (hexane:ethylacetate=2:1) to give a 1:1 mixture of ethyl4(hydroxy-(4,5-dimethyl-2-nitrophenyl)methyl)-1-(4-methoxybenzyl)-1,2,3-triazole-5-carboxylate(a-1: low polar product (LP)), and ethyl5-(hydroxy-(4,5-dimethyl-2-nitrophenyl)methyl)-1-(4-methoxybenzyl)-1,2,3-triazole-4-carboxylate(a-2: highly polar product (MP)) as a pale brown oil (5.988 g, 93.7%).

The 1:1 mixture of a-1 (LP) and a-2 (MP):

¹ H-NMR (CDCl₃): δ1.35 (3/2H, t), 1.37 (3/2H, t), 1.95 (3/2H, s), 2.23(3/2H, s), 2.34 (3/2H, s), 2.36 (3/2H, s), 3.63 (1/2H, d), 3.69 (3/2H,s), 3.78 (3/2H, s), 4.39 (2H, m), 5.22 (1/2H, d), 5.52 (1/2H, d), 5.75(1/2H, d), 5.81 (1H, d), 6.02 (1/2H, s), 6.61 (1H, d), 6.83 (1H, d),6.86(1/2H, d), 6.97 (1/2H, d), 7.09 (1H, d), 7.21 (1H, d), 7.65(1/2H,s), 7.68 (1/2H, s), 7.88 (1/2H, s).

EIMS: m/z 440 (M⁺).

(b) Manganese dioxide (15 g) was added in four portions to a solution ofthe 1:1 mixture (5.95 g, 13.5 mmole) of the compounds a-1 and a-2obtained in the preceding step (a) in methylene chloride (120 ml), andthe mixture was stirred at room temperature for 8 hours. After thereaction mixture was filtered through celite and washed with methylenechloride (100 ml), the solvent was removed under reduced pressure. Theresidue thus obtained was purified by silica gel column chromatography(hexane:ethyl acetate=4:1-2:1) to give ethyl1-(4-methoxybenzyl)-4(4,5-dimethyl-2-nitrobenzoyl)-1,2,3-triazole-5-carboxylate(b-1: LP) as a pale yellow oil (2.67 g, 45.1%) from fractions elutedwith hexane:ethyl acetate=4:1-2:1, and ethyl1-(4-methoxybenzyl)-5-(4,5-dimethyl-2-nitrobenzoyl)-1,2,3-triazole-4-carboxylate(b-2: MP) as a pale brown crystalline powder (2.50 g, 42.2%).

b-1 (LP);

¹ H-NMR (CDCl₃): δ1.36 (3H, t), 2.38 (3H, s), 2.41 (3H, s), 3.78 (3H,s), 4.41 (2H, q), 5.71 (2H, s), 6.85 (2H, d), 7.24 (2H, d), 7.34 (1H,s), 7.96 (1H, s).

EIMS: m/z 438 (M⁺).

b-2 (MP);

¹ H-NMR (CDCl₃): δ1.14 (3H, t), 2.29 (3H, s), 2.39 (3H, s), 3.77 (3H,s), 4.07 (2H, q), 5.78 (2H, s), 6.84 (2H, d), 6.94 (2H, d), 7.35 (2H,d), 7.79 (1H, s).

EIMS: m/z 439 (M⁺).

(c) A 1N aqueous sodium hydroxide solution (12 ml) was added to asolution of ethyl1-(4-methoxybenzyl)-4(4,5-dimethyl-2-nitrobenzoyl)-1,2,3-triazole-5-carboxylate(b-1) (2.63 g, 6.0 mmole) obtained in the preceding step (b) intetrahydrofuran (30 ml), and the mixture was stirred at room temperaturefor 3 hours. The reaction mixture was diluted with diethyl ether (30 ml)and water (20 ml), the organic layer was removed. The aqueous layer wasacidified with hydrochloric acid, it was extracted with ethyl acetate.

After the extract was washed with water and a saturated aqueous saline,it was dried over anhydrous magnesium sulfate, and the solvent wasremoved under reduced pressure to give1-(4-methoxybenzyl)-4(4,5-dimethyl-2-nitrobenzoyl)-1,2,3-triazole-5-carboxylicacid (c-1': LP) as a brownish oil (2.40 g, 97.5%).

c-1' (LP);

¹ H-NMR (CDCl₃): δ2.41 (3H, s), 2.46 (3H, s), 3.78 (3H, s), 6.01 (2H,s), 6.84 (2H, d), 7.32 (1H, s), 7.39 (2H, d), 8.06 (1H, s), 14.01 (1H,brs).

SIMS: m/z 411 (M⁺ +1).

The product (c-1') (1.19 g, 2.9 mmole) was then dissolved in a mixtureof ethanol (50 ml) and ethyl acetate (50 ml), 10% palladium on carbon(120 mg) was added, and the mixture was stirred under the hydrogenatmosphere at room temperature for 4.5 hours. After the reaction mixturewas filtered through celite, and the filtrate was concentrated underreduced pressure and precipitates were collected by filtration to give4(2-amino-4,5-dimethylbenzoyl)-1-(4-methoxybenzyl)-1,2,3-triazole-5-carboxylicacid (c-1: LP) as an orange crystalline powder (1.049 g, 95.1%).

c-1 (LP);

¹ H-NMR (CDCl₃): δ2.19(3H, s), 2.24 (3H, s), 3.78 (3H, s), 6.05 (2H, s),6.54 (1H, s), 6.86 (2H, d), 7.46 (2H, d), 8.43 (1H, s).

SIMS: m/z 381 (M⁺ +1).

In the same manner as above, a solution of ethyl1-(4-methoxybenzyl)-5-(4,5-dimethyl-2-nitrobenzoyl)-1,2,3-triazole-4-carboxylate(b-2) (2.48 g, 5.66 mmole) in tetrahydrofuran (30 ml) was hydrolyzedwith a 1N aqueous sodium hydroxide solution (11.3 ml) at roomtemperature for 3 hours to give1-(4-methoxybenzyl)-5-(4,5-dimethyl-2-nitrobenzoyl)-1,2,3-triazole-4-carboxylicacid (c-2': MP) as a crude product of brownish oil (2.448

c-2' (MP);

¹ H-NMR (CDCl₃): δ2.33 (3H, s), 2.38 (3H, s), 3.79 (3H, s), 5.78 (2H,s), 6.88 (2H, d), 7.09 (1H, s), 7.42 (2H, d), 7.83 (1H, s).

SIMS: m/z 411 (M⁺ +1).

Next, the product (c-2') (1.21 g) was dissolved in ethanol (100 ml) andreduced in the presence of 10% palladium on carbon (130 mg) under thehydrogen atmosphere at room temperature for 8 hours to give5-(2-amino-4,5-dimethylbenzoyl)-1-(4-methoxybenzyl)-1,2,3-triazole-4-carboxylicacid (c-2: MP) (1.089 g, 97.1%).

c-2' (MP);

¹ H-NMR (CDCl₃): δ1.83 (3H, s), 2.14 (3H, s), 3.68 (3H, s), 5.40 (2H,brs), 6.23 (1H, s), 6.45 (1H, s), 6.64 (2H, d), 7.05 (2H, d).

EIMS: m/z 380 (M⁺).

(d) Under the argon atmosphere, to a solution of4(2-amino-4,5-dimethylbenzoyl)-1-(4-methoxybenzyl)-1,2,3-triazole-5-carboxylicacid (c-1) (495 mg, 1.30 mmole) in methylene chloride (13 ml) were addedunder ice-cooling tributylamine (341 μl, 1.43 mmole),2-fluoro-1-methylpyridinium p-toluenesulfonate (442 mg, 1.56 mmole) and3,4-dihydro-2H-pyrido 1,2-a!pyrimidin-2-one (240 mg, 1.62 mmole) in thissequence, and the mixture was stirred under ice-cooling for 1 hour andat room temperature for further 1 hour.

The reaction mixture was diluted with methylene chloride and water andstirred under water-cooling for 15 minutes. Resulting precipitates werecollected by filtration, washed with water followed by methylenechloride, and desiccated to give3-(4-methoxybenzyl)-7,8-dimethyl-4(5H),10-dioxo-3H-1,2,3-triazolo 5,4-c!1!benzazepine (d-1: LP) as a colorless crystalline powder (190 mg,40.3%).

d-1 (LP);

¹ H-NMR (DMSO-d₆): δ2.29 (6H, s), 3.72 (3H, s), 6.08 (2H, s), 6.89 (2H,d), 7.30 (1H, brs), 7.31 (2H, d), 8.00 (1H, s), 11.39 (1H, s).

SIMS: m/z 363 (M⁺ +1).

Also, in the same manner as above, starting from5-(2-amino-4,5-dimethylbenzoyl)-1-(4-methoxybenzyl)-1,2,3-triazole-5-carboxylicacid (c-2) (495 mg, 1.30 mmole)1-(4-methoxybenzyl)-7,8-dimethyl-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine (d-2: MP) as a colorless crystalline powder (295 mg,62.6%).

d-2 (MP);

¹ H-NMR (DMSO-d₆): δ2.27 (3H, s), 2.28 (3H, s), 3.72 (3H, s), 6.01 (2H,s), 6.89 (2H, d), 7.28 (1H, d), 7.31 (1H, s), 7.93 (1H, s), 11.25 (1H,s).

SIMS: m/z 363 (M⁺ +1).

(e) To 3-(4-methoxybenzyl)-7,8-dimethyl-4(5H),10-dioxo-3H-1,2,3-triazolo5,4-c! 1!benzazepine (d-1) (185 mg, 0.51 mmole) were added anisole (0.4ml) and trifluoroacetic acid (4.0 ml), and the mixture was stirred at60° C. for 1 hour. The solvent was then removed under reduced pressure.The residue thus obtained was washed with diisopropyl ether, anddesiccated to give the title compound,7,8-dimethyl-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c! 1!benzazepine (e)as a crude product of pale yellow powder (178 mg).

(e);

¹ H-NMR (DMSO-d₆): δ2.30 (6H, s), 7.35 (1H, s), 8.05 (1H, s), 11.29 (1H,s).

FDMS: m/z 241 (M⁺ -1).

Also, in the same way as described above,1-(4-methoxybenzyl)-7,8-dimethyl-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine (d-2) (283 mg, 0.781 mmole) was subjected to deprotectionwith anisole (0.6 ml) and trifluoroacetic acid (6 ml) and post-treatmentto give the crude product of the same title compound (e) as above (254mg).

After the crude product (425 mg) thus obtained was suspended in water(12 ml) and dissolved in a 1N aqueous sodium hydroxide solution (3.2ml), the solution was purified with DIAION HP-20 (120 ml,water:acetone=20:1-10:1), and lyophilized to give the sodium salt of thetitle compound, 7,8-dimethyl-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine (e') (311 mg, 91.2%) as a colorless powder.

(e');

¹ H-NMR (DMSO-d₆): δ2.25 (3H, s), 2.26 (2H, s), 7.25 (1, s), 8.02 (1H,s), 10.41 (1H, s).

SIMS: m/z 241 (M⁺ -Na).

Example 45

8-methoxy-7-methyl-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c! 1!benzazepine

(a) 1.5N butyllithium (3.10 ml, 4.65 mmole) was added under the argonatmosphere to a solution of diisopropylamine (0.70 ml, 4.99 mmole) intetrahydrofuran (5 ml) at -78° C., and the mixture was stirred for 1hour. To the reaction mixture were next added a solution of ethylpropiolate (0.39 ml, 3.84 mmole) in tetrahydrofuran (2 ml) and asolution of 5-methoxy 4-methyl-2-nitrobenzaldehyde (542 mg, 2.78 mmole)in tetrahydrofuran (7 ml) in this sequence, and the reaction mixture wasstirred at -78° C. for further 2 hours. After a solution of acetic acid(0.9 ml, 15.7 mmole) in tetrahydrofuran (3 ml) followed by water wereadded, the reaction mixture was extracted with ethyl acetate.

The organic layer was washed with dilute hydrochloric acid, water, asaturated aqueous sodium hydrogen carbonate solution and a saturatedaqueous saline in this sequence. After the organic layer was dried overanhydrous magnesium sulfate, the solvent was removed under reducedpressure to give ethyl4-hydroxy-4(5-methoxy-4-methyl-2-nitrophenyl)-2-butynoate as an oil (940mg). To the solution of the product,4-hydroxy-4(5-methoxy-4-methyl-2-nitrophenyl)-2-butynoate was added4-methoxybenzyl-azide (1.36 g, 8.33 mmole), and the mixture was stirredat 100° C. overnight.

After the reaction mixture was cooled to room temperature, it waspurified by silica gel column chromatography (hexane:ethyl acetate=2:1)to give a 1:1 mixture of ethyl4(hydroxy-(5-methoxy-4-methyl-2-nitrophenyl)methyl)-1-(4-methoxybenzyl)-1,2,3-triazole-5-carboxylate(a-1: low polar product (LP)), and ethyl5-(hydroxy-(5-methoxy-4-methyl-2-nitrophenyl)methyl)-1-(4-methoxybenzyl)-1,2,3-triazole-4-carboxylate(a-2: highly polar product (MP)) (686 mg, 54%).

The 1:1 mixture of a-1 (LP) and a-2 (MP):

¹ H-NMR (CDCl₃): δ1.26 (3/2H, t), 1.38 (3/2H, t), 2.17 (3/2H, s), 2.26(3/2H, s), 3.46 (3/2H, s), 3.63 (1/2H, d), 3.71 (3/2H, s), 3.78 (3/2H,s), 3.93 (3/2H, s), 4.35-4.50 (2H, m), 5.12 (1/2H, d), 5.47 (1/2H, d),5.74 (1/2H, d), 5.78 (1/2H, d), 5.84 (1/2H,d) 6.09 (1/2H, s), 6.65 (1H,d), 6.83 (1H, d), 6.96 (1/2H, d), 7.04 (1H, d), 7.08 (1/2H, d), 7.21(1H, d), 7.42 (1/2H, s), 7.80 (1/2H, d), 8.00 (1/2H, d).

EIMS: m/z 446 (M⁺).

(b) Manganese dioxide (1.26 g) was added to the solution of the 1:1mixture (631 mg, 1.38 mmole) of the compounds a-1 and a-2 obtained inthe preceding step (a) in methylene chloride (15 ml), and the mixturewas stirred at room temperature for 13 hours. Additional amount ofmanganese dioxide (1.26 g) was added in two portions, and the mixturewas stirred at room temperature for 3 hours. After the reaction mixturewas filtered through celite and washed with ethyl acetate, the solventwas removed under reduced pressure. The residue thus obtained waspurified by silica gel column chromatography (hexane:ethyl acetate=5:1)to give ethyl1-(4-methoxybenzyl)-4-(5-methoxy-4-methyl-2-nitrobenzoyl)-1,2,3-triazole-5-carboxylate(b-1: LP) as a yellow oil (256 mg, 41%) as well as ethyl1-(4-methoxybenzyl)-5-(5-methoxy-4-methyl-2-nitrobenzoyl)-1,2,3-triazole-4-carboxylate(b-2: MP) as a pale yellow crystalline powder (310 mg, 49%).

b-1 (LP);

¹ H-NMR (CDCl₃): δ1.38 (3H, t), 2.32 (3H, s), 3.78 (3H, s), 3.93 (3H,s), 4.41 (2H, q), 5.71 (2H, s), 6.85 (2H, d), 6.90 (1H, s), 7.24 (2H,d), 8.02 (1H, d).

EIMS: m/z 454 (M⁺).

b-2 (MP);

¹ H-NMR (CDCl₃): δ1.16 (3H, t), 2.31 (3H, s), 3.79 (3H, s), 3.86 (3H,s), 4.07 (2H, q), 5.82 (2H, s), 6.69 (1H, s), 6.88 (2H, d), 7.42 (2H,d), 7.89 (1H, d).

EIMS: m/z 454 (M⁺).

(c) A 1N aqueous sodium hydroxide solution (1.1 ml) was added to asolution of ethyl1-(4-methoxybenzyl)-4(5-methoxy-4-methyl-2-nitrobenzoyl)-1,2,3-triazole-5-carboxylate(b-1) (243 mg, 0.535 mmole) obtained in the preceding step (b) intetrahydrofuran (6 ml), and the mixture was stirred at room temperaturefor 4 hours. The reaction mixture was diluted with ether, and water wasadded. The aqueous layer was acidified with hydrochloric acid, it wasextracted with ethyl acetate, and washed with water and a saturatedaqueous saline. After the organic layer was dried over anhydrousmagnesium sulfate, and the solvent was removed under reduced pressure togive1-(4-methoxybenzyl)-4(5-methoxy-4-methyl-2-nitrobenzoyl)-1,2,3-triazole-5-carboxylicacid (c-1': LP) as a pale yellow crystalline powder (204 mg, 89%). Next,1-(4-methoxybenzyl)-4-(5-methoxy-4-methyl-2-nitrobenzoyl)-1,2,3-triazole-5-carboxylicacid (c-1': LP) (200 mg, 0.469 mmole) thus obtained was dissolved in amixed solvent of ethanol (12 ml) and ethyl acetate

(12 ml), 10% palladium on carbon (25 mg) was added, and the mixture wasstirred under the hydrogen atmosphere at room temperature for 6.5 hours.After the reaction mixture was filtered through celite, the filtrate wasconcentrated under reduced pressure, and precipitates were collected byfiltration to give4(2-amino-5-methoxy-4-methylbenzoyl)-1-(4-methoxybenzyl)-1,2,3-triazole-5-carboxylicacid (c-1LP) as a red crystalline powder (178 mg, 96%).

c-1' (LP);

¹ H-NMR (CDCl₃): δ2.36 (3H, s), 3.77 (3H, s), 3.94 (3H, s), 6.02 (2H,s), 6.84 (2H, d), 6.85 (1H, s), 7.40 (2H, d), 8.10 (1H, s), 13.85 (1H,brs).

SIMS: m/z 427 (M⁺ +1).

c-1 (LP);

¹ H-NMR (CDCl₃): δ2.24 (3H, s), 3.78 (3H, s), 3.82 (3H, s), 6.06 (2H,s), 6.54 (1H, s), 6.86 (2H, d), 7.45 (2H, d), 8.36 (1H, s).

SIMS: m/z 397 (M⁺ +1).

In the same manner as above, a solution of ethyl1-(4-methoxybenzyl)-5-(5-methoxy-4-methyl-2-nitrobenzoyl)-1,2,3-triazole-4-carboxylate(b-2) (288 mg, 0.638 mmole) in tetrahydrofuran (7 ml) was hydrolyzedwith a 1N aqueous sodium hydroxide solution (1.3 ml) at room temperaturefor 4.5 hours to give1-(4-methoxybenzyl)-5-(5-methoxy-4-methyl-2-nitrobenzoyl)-1,2,3-triazole-4-carboxylicacid (c-2': MP) (256 mg, 94%).

Next,1-(4-methoxybenzyl)-5-(5-methoxy-4-methyl-2-nitrobenzoyl)-1,2,3-triazole-4-carboxylicacid (c-2': MP) (252 mg, 0.591 mmole) was dissolved in a mixed solventof ethanol (10 ml) and ethyl acetate (10 ml), and reduced in thepresence of 10% palladium on carbon (31 mg) under the hydrogenatmosphere at room temperature overnight to give5-(2-amino-5-methoxy-4-methylbenzoyl)-1-(4-methoxybenzyl)-1,2,3-triazole-4-carboxylicacid (c-2: MP) (216 mg, 92%).

c-2' (MP);

¹ H-NMR (CDCl₃): δ2.31 (3H, s), 3.81 (3H, s), 3.90 (3H, s), 5.81 (2H,s), 6.81 (1H, s), 6.91 (2H, d), 7.48 (2H, d), 7.92 (1H, s).

SIMS: m/z 427 (M⁺ +1).

c-2' (MP);

¹ H-NMR (CDCl₃): δ2.13 (3H, s), 3.29 (3H, s), 3.68 (3H, s), 5.45 (2H,brs), 5.82 (1H, s), 6.47 (1H, s), 6.64 (2H, d), 7.06 (2H, d).

FDMS: m/z 396 (M⁺).

(d) Under the argon atmosphere, to a solution of4(2-amino-5-methoxy-4-methylbenzoyl)-1-(4-methoxybenzyl)-1,2,3-triazole-5-carboxylicacid (c-1) (173 mg, 0.436 mmole) in methylene chloride (4 ml) were addedunder ice-cooling tributylamine (0.11 ml, 0.462 mmole),2-fluoro-1-methylpyridinium p-toluenesulfonate (136 mg, 0.480 mmole) and3,4-dihydro-2H-pyrido 1,2-a!pyrimidin-2-one (78 mg, 0.526 mmole) in thissequence, and the mixture was stirred under ice-cooling for 1 hour andfurther at room temperature overnight.

The reaction mixture was diluted with water, and resulting precipitateswere collected by filtration, washed with methylene chloride and water,and desiccated to give8-methoxy-3-(4-methoxybenzyl)-7-methyl-4(5H),10-dioxo-3H-1,2,3-triazolo5,4-c! 1!benzazepine (d-1: LP) as a pale yellow crystalline powder.Also, the filtrate was extracted with methylene chloride, washed withdilute hydrochloric acid, a saturated aqueous sodium hydrogen carbonatesolution and a saturated aqueous saline, dried over anhydrous sodiumsulfate, and the solvent was removed under reduced pressure. Theresulting precipitates were collected by filtration to give8-methoxy-3-(4-methoxybenzyl)-7-methyl-4(5H),10-dioxo-3H-1,2,3-triazolo5,4-c! 1!benzazepine (d-1: LP) in a total amount of 25 mg (15%).

d-1 (LP);

¹ H-NMR (DMSO-d₆): δ2.21 (3H, s), 3.71 (3H, s), 3.87 (3H, s), 6.09 (2H,s), 6.90 (2H, d), 7.30 (2H, d), 7.35 (1H, s), 7.64 (1H, s), 11.39 (1H,s).

SIMS: m/z 379 (M⁺ +1).

Also, in the same manner as above, starting from5-(2-amino-5-methoxy-4-methylbenzoyl)-1-(4-methoxybenzyl)-1,2,3-triazole-4-carboxylicacid (c-2) (216 mg, 0.545 mmole),8-methoxy-1-(4-methoxybenzyl)-7-methyl-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine (d-2: MP) (143 mg, 69%).

d-2 (MP);

¹ H-NMR (DMSO-d₆): δ2.21 (3H, s), 3.71 (3H, s), 3.86 (3H, s), 6.02 (2H,s), 6.91 (2H, d), 7.29 (2H, d), 7.36 (1H, s), 7.56 (1H, s), 11.26 (1H,s).

EIMS: m/z 378 (M⁺).

(e) To8-methoxy-1-(4-methoxybenzyl)-7-methyl-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine (d-2) (140 mg, 0.370 mmole) were added anisole (0.4ml) and trifluoroacetic acid (4.0 ml), and the mixture was stirred at60° C. for 2.5 hours. The solvent was then removed under reducedpressure. The residue thus obtained was washed with diethyl ether andwater, and desiccated to give the title compound,8-methoxy-7-methyl-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c! 1!benzazepine(e) as a yellow powder (81 mg, 85%). The product,8-methoxy-7-methyl-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c! 1!benzazepine(e) (76 mg, 0.294 mmole) was dissolved in a 1N aqueous sodium hydroxidesolution, and purified on DIAION HP-20 (water:acetone=9:1) to give thesodium salt of the title compound,8-methoxy-7-methyl-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine, (e') as a pale yellow powder (82 mg, 80%).

(e);

¹ H-NMR (DMSO-d₆): δ2.21 (3H, s), 3.86 (3H, s), 7.37 (1H, s), 7.66 (1H,s), 11.28 (1H, s).

(e');

SIMS: m/z 258 (M⁺ -Na+1).

The compound prepared in Example 4 was synthesized with reagents shownin Example 46 according to the procedure described in Example 46.

Example 46

7-methyl-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c! 1!benzazepine

(a) Starting from 4-methyl-2-nitrobenzaldehyde and ethyl propiolate,ethyl 4-hydroxy-4(4-methyl-2-nitrophenyl)-2-butynoate was prepared withthe following reagents instead of a solution of 1.56N butyllithium inhexane.

(a-1) To a solution of ethyl propiolate (6.6 ml, 65 mmole) intetrahydrofuran (70 ml) was added at -65° C. under the argon atmospherea solution of 1.0M lithium bistrimethylsilylamide in tetrahydrofuran (65ml, 65 mmole), and the mixture was stirred for 20 minutes. A solution of4-methyl-2-nitrobenzaldehyde (8.3 g, 50 mmole) in tetrahydrofuran (30ml) was added, and the reaction mixture was further stirred at 65° C.for 3 hours. To the reaction mixture was added a saturated aqueoussodium hydrogen carbonate solution (80 ml) or a solution of acetic acid(13.0 ml, 220 mmole) in tetrahydrofuran (20 ml), followed by water, andthe aqueous layer was extracted with ethyl acetate. The organic layerwas washed with dilute hydrochloric acid, a saturated aqueous sodiumhydrogen carbonate solution and a saturated aqueous saline in thissequence, dried over anhydrous sodium sulfate, and the solvent wasremoved under reduced pressure to give ethyl4-hydroxy-4(4-methyl-2-nitrophenyl)-2-butynoate as an oil (13.5 g).

(a-2) To a solution of ethyl propiolate (1.2 ml, 12.0 mmole) intetrahydrofuran (20 ml) was added at -65° C. under the argon atmospherea solution of 2.0M lithium diisopropylamide in a mixed solvent ofheptane-tetrahydrofuran-ethylbenzene (6.0 ml, 12.0 mole), and themixture was stirred for 20 minutes. A solution of4-methyl-2-nitrobenzaldehyde (1.65 g, 10 mmole) in tetrahydrofuran (10ml) was added, and the reaction mixture was further stirred at 65° C.for 3 hours. To the reaction mixture was added a saturated aqueousammonium chloride solution (20 ml) or a solution of acetic acid (13.0ml, 220 mmole) in tetrahydrofuran (20 ml), followed by water, and theaqueous layer was extracted with ethyl acetate. The organic layer waswashed with dilute hydrochloric acid, a saturated aqueous sodiumhydrogen carbonate solution and a saturated aqueous saline in thissequence, dried over anhydrous magnesium sulfate, and the solvent wasremoved under reduced pressure to give ethyl4-hydroxy-4(4-methyl-2-nitrophenyl)-2-butynoate as an oil (2.60 g).

¹ H-NMR (CDCl₃): δ1.31 (1H, t), 2.46 (3H, s), 3.37 (1H, d), 4.24 (2H,q), 6.10 (1H, d), 7.51 (1H, dd), 7.78 (1H, d), 7.86 (1H, d).

FDMS: m/z 264 (M⁺ +1).

(b) Ethyl 4-hydroxy-4(4-methyl-2-nitrophenyl)-2-butynoate (6.9 g, 26mmole) obtained in the preceding step (a) was dissolved in toluene (30ml), 4-methoxybenzylazide (8.20 g, 50.0 mmole) was added, and themixture was stirred under heating at 60° C. for 6 hours. After thereaction mixture was cooled to room temperature, the solvent was removedby distillation. Ethyl acetate (4 ml) was added, and hexane (80 ml) wasfurther added. Precipitates were collected by filtration, washed withhexane, and desiccated to give a 1:1 mixture of ethyl4-(hydroxy(4-methyl-2-nitrophenyl)methyl)-1-(4-methoxybenzyl)-1,2,3-triazole-5-carboxylateand ethyl5-(hydroxy-(4-methyl-2-nitrophenyl)methyl)-1-(4-methoxybenzyl)-1,2,3-triazole-4-carboxylateas a yellow crystalline powder (10.0 g, 94.0% for two steps) which wasthe same compound as a obtained in Example 4.

(c) To a solution of the 1:1 mixture of ethyl4(hydroxy(4-methyl-2-nitrophenyl)methyl)-1-(4-methoxybenzyl)-1,2,3-triazole-5-carboxylateand ethyl5-(hydroxy-(4-methyl-2-nitrophenyl)methyl)-1-(4-methoxybenzyl)-1,2,3-triazole-4-carboxylate(16.0 g, 37.6 mmole) in methylene chloride (180 ml) was added manganesedioxide (49.0 g), and the mixture was stirred at room temperature for 15hours. The reaction mixture was filtered through celite, washed withmethylene chloride (200 ml), and the solvent was removed under reducedpressure. The residue thus obtained was desiccated to give a 1:1 mixtureof1-(4-methoxybenzyl)-4-(4-methyl-2-nitrobenzoyl)-1,2,3-triazole-5-carboxylate(Example 4, b-1) and1-(4-methoxybenzyl)-5-(4-methyl-2-nitrobenzoyl)-1,2,3-triazole-4-carboxylate(Example 4, b-2) as a brown oil (15.5 g, 97.0%).

¹ H-NMR (CDCl₃): δ1.14 (3/2H, t), 1.37 (3/2H, t), 2.51 (3/2H, s), 2.53(3/2H, s), 3.77 (3/2H, s), 3.79 (3/2H, s), 4.08 (1H, q), 4.43 (1H, q),5.72 (1H, s), 5.78 (1H, s), 6.80-6.87 (2H, m), 7.18-7.27 (3/2H, m),7.34-7.37 (1H, m), 7.43-7.46 (1/2H, m), 7.50-7.59 (1H, m), 7.80 (1/2H,s), 7.90 (1/2H, s).

SIMS: m/z 425 (M⁺ +1).

(d) The 1:1 mixture of ethyl1-(4-methoxybenzyl)-4-(4-methyl-2-nitrobenzoyl)-1,2,3-triazole-5-carboxylateand ethyl1-(4-methoxybenzyl)-5-(4-methyl-2-nitrobenzoyl)-1,2,3-triazole-4-carboxylate(15.5 g, 36.6 mmole) was dissolved in ethyl acetate (350 ml), 10%palladium on carbon (1.5 g) was added, and the mixture was stirred underthe hydrogen atmosphere at room temperature for 8.5 hours.

After the reaction mixture was filtered through celite, the filtrate wasconcentrated under reduced pressure. Precipitates were collected byfiltration to give a 1:1 mixture of ethyl4-(2-amino-4-methylbenzoyl)-1-(4-methoxybenzyl)-1,2,3-triazole-5-carboxylateand ethyl5-(2-amino-4-methylbenzoyl)-1-(4-methoxybenzyl)-1,2,3-triazole-4-carboxylateas a yellow oil (13.8 g, 96%).

¹ H-NMR (CDCl₃): δ1.07-1.13 (3H, m), 2.23 (3/2H, s), 2.26 (3/2H, s),3.69 (3/2H, s), 3.79 (3/2H, s), 4.17-4.24 (2H, m), 5.45 (1H, brs), 5.85(1H, s), 6.17-6.20 (1/2H, m), 6.32-6.39 (2H, m), 6.46-6.49 (1H, m),6.57-6.59 (1/2H, m), 6.65-6.68 (1H, m), 6.87 (1H, d), 7.08 (1H, d),7.26-7.28 (1H, m), 7.34-7.36 (1H, m).

SIMS: m/z 395 (M⁺ +1).

(e) The 1:1 mixture of ethyl4-(2-amino-4-methylbenzoyl)-1-(4-methoxybenzyl)-1,2,3-triazole-5-carboxylateand ethyl5-(2-amino-4-methylbenzoyl)-1-(4-methoxybenzyl)-1,2,3-triazole-4-carboxylate(2.72 g, 6.9 mmole) was dissolved in methanol (7 ml), a solution of 28%sodium methoxide in methanol (3.4 ml, 13.9 mmole) was added, and themixture was stirred under the argon atmosphere at room temperature for16 hours.

The reaction mixture was diluted with 1N hydrochloric acid (15 ml) andmethanol (20 ml) or diethyl ether (20 ml). The resulting precipitateswere collected by filtration, washed with methanol or diethyl ether, anddesiccated to give a 1:1 mixture of3-(4-methoxybenzyl)-7-methyl-4(5H),10-dioxo-3H-1,2,3-triazolo 4,5-c!1!benzazepine (Example 4, d-1) and1-(4-methoxybenzyl)-7-methyl-4(5H),10-dioxo-1H-1,2,3-triazolo 5,4-c!1!benzazepine (Example 4, d-2) as a yellow crystalline powder (1.85 g,77%).

¹ H-NMR (CDCl₃): δ2.36 (3H, s), 3.71 (3H, s), 5.99 (1H, s), 6.07 (1H,s), 6.89-6.91 (2H, m), 7.12 (1/2H, d), 7.17 (1/2H, d), 7.27-7.32 (3H,m), 8.07 (1/2H, d), 8.13 (1/2H, d), 11.3 (1/2H, s), 11.4 (1/2H, s).

SIMS: m/z 349 (M⁺ +1).

(f) To the 1:1 mixture of3-(4-methoxybenzyl)-7-methyl-4(5H),10-dioxo-3H-1,2,3-triazolo 4,5-c!1!benzazepine and1-(4-methoxybenzyl)-7-methyl-4(5H),10-dioxo-1H-1,2,3-triazolo 5,4-c!1!benzazepine (4.8 g, 13.8 mmole) obtained in the preceding step (e)were added anisole (10 ml) and trifluoroacetic acid (100 ml), and themixture was stirred at 70° C. for 3 hours.

After the reaction solvent was removed under reduced pressure, theresidue was diluted with water (50 ml) and isopropyl ether (50 ml) ordiethyl ether (50 ml). The resulting precipitates were collected byfiltration, washed with isopropyl ether or diethyl ether and desiccatedto give the title compound, 7-methyl-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine as a yellow crystalline powder (3.0 g, 95%) whichwas the same as the title compound in Example 4.

(g) 7-methyl-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c! 1!benzazepine (1.14g, 5 mmole) obtained in the preceding step (f) was dissolved indimethylsulfoxide (15 ml), a 28% methanolic sodium methoxide solution(1.25 ml, 4.9 mmole), and the mixture was stirred at room temperaturefor 30 minutes. To the reaction mixture was added acetone (100 ml) ordiethyl ether (200 ml). The resulting precipitates were collected byfiltration, washed with acetone or diethyl ether, and desiccated.

After the precipitates were dissolved in water (120 ml), the solutionwas subjected to purification with DIAION HP-20 (water:acetone=9:1-7:3)and lyophilized to give the sodium salt of the title compound,7-methyl-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c! 1!benzazepine as acolorless powder (1.24 g, 99%).

¹ H-NMR (D₂ O): δ1.87 (3H, s), 6.50 (1H, s), 6.58 (1H, dz), 7.76 (1H,d).

Also, the compound of Example 46 can be prepared, as is shown inExamples 37 and 38, from the mixture of3-(4-methoxybenzyl)-7-methyl-4(5H),10-dioxo-3H-1,2,3-triazolo 5,4-c!1!benzazepine and1-(4-methoxybenzyl)-7-methyl-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine obtained in Example 46 (c) according to the same reactionsas in Example 4.

Example 47

3-(4-methoxybenzyl)-7-methyl-4(5H),10-dioxo-3H-1,2,3-triazolo 5,4-c!1!benzazepine, and1-(4-methoxybenzyl)-7-methyl-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine

(a) To a solution of the 1:1 mixture of ethyl1-(4-methoxybenzyl)-4-(4-methyl-2-nitrobenzoyl)-1,2,3-triazole-5-carboxylateand ethyl1-(4-methoxybenzyl)-5-(4-methyl-2-nitrobenzoyl)-1,2,3-triazole-4-carboxylate(7.24 g, 17.0 mmole) in tetrahydrofuran (80 ml) was added a 1N aqueoussodium hydroxide solution (45 ml), and the mixture was stirred at roomtemperature for 2 hours.

After the reaction mixture was acidified with hydrochloric acid, it wasextracted with ethyl acetate and washed with a saturated aqueous saline.The organic layer was dried over anhydrous sodium sulfate, and thesolvent was removed under reduced pressure to give a 3:2 mixture of1-(4-methoxybenzyl)-4-(4-methyl-2-nitrobenzoyl)-1,2,3-triazole-5-carboxylicacid (Example 4, c-1') and1-(4-methoxybenzyl)-5-(4-methyl-2-nitrobenzoyl)-1,2,3-triazole-4-carboxylicacid (Example 4, c-2') as a colorless crystalline powder (6.3 g, 93%).The product was then dissolved in a mixed solvent of ethanol (125 ml)and ethyl acetate (250 ml), 10% palladium on carbon (680 mg) was added,and the mixture was stirred under the argon atmosphere at roomtemperature for 10 hours.

After the reaction mixture was filtered through celite and desiccated togive a 3:2 mixture of4-(2-amino-4-methylbenzoyl)-1-(4-methoxybenzyl)-1,2,3-triazole-5-carboxylicacid (Example 4, c-2) and5-(2-amino-4-methylbenzoyl)-1-(4-methoxybenzyl)-1,2,3-triazole-4-carboxylicacid (Example 4, c-1) as a yellow crystalline powder (5.6 g, 96%).

¹ H-NMR (CDCl₃): δ2.23-2.42 (3H, m), 3.69-3.80 (3H, m), 5.40-5.62 (2H,m), 6.04 (4/5H, s), 6.19 (2/5H, d), 6.46 (3/5H, s), 6.50-6.60 (7/5H, m),6.67 (6/5H, d), 6.86 (4/5H, d), 7.07 (6/5H, d), 7.45 (4/5H, d), 8.60(2/5H, d).

FDMS: m/z 366 (M⁺).

(b) To a solution of the 3:2 mixture of4-(2-amino-4-methylbenzoyl)-1-(4-methoxybenzyl)-1,2,3-triazole-5-carboxylicacid and5-(2-amino-4-methylbenzoyl)-1-(4-methoxybenzyl)-1,2,3-triazole-4-carboxylicacid (2.2 g, 6 mmole) in methylene chloride (30 ml) under ice-coolingwere added under the argon atmosphere tributylamine (1.57 ml, 6.6mmole), 2-chloro-1-methylpyridinium p-toluenesulfonate (2.16 g, 7.2mmole) and 3,4-dihydro-2H-pyrido 1,2-a!pyrimidin-2-one (1.16 g, 7.8mmole) in this sequence, and the mixture was stirred at room temperaturefor 1 hour and further at 50° C. for 1 hour.

The reaction mixture was diluted with ethyl acetate and water, andresulting precipitates were collected by filtration, washed with diethylether, and desiccated to give a 3:2 mixture of3-(4-methoxybenzyl)-7-methyl-4(5H),10-dioxo-3H-1,2,3-triazolo 5,4-c!1!benzazepine (Example 4, d-1) and1-(4-methoxybenzyl)-7-methyl-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine (Example 4, d-2) as a pale yellow crystalline powder (0.9g, 43%).

¹ H-NMR (DMSO-d₆): δ2.36 (3H, s), 3.71 (3H, s), 5.99 (6/5H, s), 6.07(4/5H, s), 6.89-6.91 (2H, m),7.12 (3/5H, d, J=8.4 Hz), 7.17 (2/5H, d,J=8.4 Hz), 7.27-7.33 (3H, m), 8.07 (3/5H, d), 8.13 (2/5H, d), 11.3(3/5H, s), 11.4 (2/5H, s).

SIMS: m/z 349 (M⁺ +1).

Also, the same compound as that prepared in Example 47 (b) was obtainedin the following manner.

(c-1) After the 3:2 mixture of4-(2-amino-4-methylbenzoyl)-1-(4-methoxybenzyl)-1,2,3-triazole-5-carboxylicacid and5-(2-amino-4-methylbenzoyl)-1-(4-methoxybenzyl)-1,2,3-triazole-4-carboxylicacid (14 g, 38.3 mmole) was dissolved in methylene chloride (50 ml) andtriethylamine (5.53 ml, 40 mmole), the solvent was removed under reducedpressure to give the triethylamine salt (17.0 g, 95%).

To a solution of the triethylamine salt (4.67 g, 10 mmole) in methylenechloride (100 ml) were added under ice-cooling triethylamine (4.15 ml,30 mmole), followed by 2-chloro-1-methylpyridinium iodide (3.83 g, 15mmole), and the mixture was stirred at room temperature for 15 hours.The reaction mixture was diluted with ethyl acetate and water, and theresulting precipitates were collected by filtration, pulverized withdiethyl ether, and desiccated to give a 3:2 mixture of3-(4-methoxybenzyl)-7-methyl-4(5H),10-dioxo-3H-1,2,3-triazolo 5,4-c!1!benzazepine and1-(4-methoxybenzyl)-7-methyl-4(5H),10-dioxo-1H-1,2,3-triazolo 5,4-c!1!benzazepine as a yellow crystalline powder (2.1 g, 60%).

(c-2) The triethylamine salt of the 3:2 mixture of4(2-amino-4-methylbenzoyl)-1-(4-methoxybenzyl)-1,2,3-triazole-5-carboxylicacid and5-(2-amino-4-methylbenzoyl)-1-(4-methoxybenzyl)-1,2,3-triazole-4-carboxylicacid (9.3 g, 20 mmole) was dissolved in N,N-dimethylformamide (100 ml),triethylamine (5.6 ml, 40 mmole), followed by(benzotriazol-1-yl)oxytris(dimethylamino)phosphonium hexafluorophosphate(13.3 g, 30 mmole), and the mixture was stirred at room temperature for15 hours.

The reaction mixture was diluted with ethyl acetate and water, and theresulting precipitates were collected by filtration, pulverized withdiethyl ether, and desiccated to give the title compound, the 3:2mixture of 3-(4-methoxybenzyl)-7-methyl-4(5H),10-dioxo-3H-1,2,3-triazolo5,4-c! 1!benzazepine and1-(4-methoxybenzyl)-7-methyl-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine, as a yellow crystalline powder (4.23 g, 61%).

The compound d-1 of Example 4 can be also prepared with use of themethod described in Example 48.

Example 48

3-(4-methoxybenzyl)-7-methyl-4(5H),10-dioxo-3H-1,2,3-triazolo 5,4-c!1!benzazepine

(a) Diphenylphosphorylazide (0.016 ml, 0.075 mmole) was added underice-cooling to a solution of4-(2-amino-4-methylbenzoyl)-1-(4-methoxybenzyl)-1,2,3-triazole-5-carboxylicacid (17 mg, 0.05 mmole) in N,N-dimethylformamide (2 ml), and themixture was stirred at room temperature for 45 hours. The reactionmixture was diluted with ethyl acetate and water. The resultingprecipitates were collected by filtration, washed with diethyl ether,and desiccated to give the title compound,3-(4-methoxybenzyl)-7-methyl-4(5H),10-dioxo-3H-1,2,3-triazolo 5,4-c!1!benzazepine, as a yellow crystalline powder (10.4 mg, 60%).

(b) To a solution of4-(2-amino-4-methylbenzoyl)-1-(4-methoxybenzyl)-1,2,3-triazole-5-carboxylicacid (17 mg, 0.05 mmole) in N,N-dimethylformamide (1 ml) were addedunder ice-cooling 1-hydroxybenzotriazole (8.1 mg, 0.06 mmole) andN-methylmorpholine (0.007 ml, 0.06 mmole) and1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (8.1 mg,0.06 mmole), and the mixture was stirred at room temperature for 45hours. The reaction mixture was diluted with ethyl acetate and water.The resulting precipitates were collected by filtration, washed withdiethyl ether, and desiccated to give the title compound,3-(4-methoxybenzyl)-7-methyl-4(5H),10-dioxo-3H-1,2,3-triazolo 5,4-c!1!benzazepine, as a yellow crystalline powder (8.5 mg, 53%).

The compound shown in Example 9 can be also prepared according to themethod described in Example 49.

Example 49

5-methyl-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c! 1!benzazepine

(a) Under the argon atmosphere, N-methylaniline (0.1 ml, 0.923 mmole)and pyridine (0.32 ml, 3.96 mmole) were added to a solution of5-ethoxycarbonyl-1-(4-methoxybenzyl)-1,2,3-triazole-4-carboxylic acid(311 mg, 1.02 mmole) in methylene chloride (3 ml). To the reactionmixture, which had been cooled to -30° C., was added a solution ofphosphorus oxychloride (192 mg, 1.25 mmole) in methylene chloride (0.5ml). After the mixture was stirred at -30° C. for 1 hour, the reactionwas quenched by adding water. The reaction mixture was extracted withethyl acetate, and the organic layer was washed with dilute hydrochloricacid, a saturated aqueous sodium hydrogen carbonate and a saturatedaqueous saline. The organic layer was dried over anhydrous magnesiumsulfate, and the solvent was removed by distillation. The residue thusobtained was purified by silica gel column chromatography (hexane:ethylacetate=1:1) to give ethyl1-(4-methoxybenzyl)-4(N-methyl-N-phenylcarbamoyl)-1,2,3-triazole-5-carboxylateas a yellow crystalline powder (329 mg, 90.4%).

EIMS: m/z 394 (M⁺).

(b) Ethyl1-(4-methoxybenzyl)-4-(N-methyl-N-phenylcarbamoyl)-1,2,3-triazole-5-carboxylate(331 mg, 0.839 mmole) obtained in the preceding step (a) was dissolvedin a mixed solvent of ethanol (1 ml) and water (3.5 ml). A 1N aqueoussodium hydroxide solution (1.5 ml) was added to the reaction mixture,and the resulting mixture was stirred at room temperature for 28.5hours.

After the reaction mixture was diluted with diethyl ether, the aqueouslayer was separated, acidified with hydrochloric acid, extracted withethyl acetate, and washed with a saturated aqueous saline. After theorganic layer was dried over anhydrous magnesium sulfate, the solventwas removed under reduced pressure to give1-(4-methoxybenzyl)-4-(N-methyl-N-phenylcarbamoyl)-1,2,3-triazole-5-carboxylicacid as a yellow crystalline powder (276 mg, 89.8%).

¹ H-NMR (CDCl₃): δ3.44 (3H, s), 3.81 (3H, s), 6.95 (2H, d), 7.40 (2H,d).

SIMS: m/z 367 (M⁺ +1).

(c) Under the argon atmosphere, oxalyl chloride (0.07 ml, 0.802 mmole)and dimethylformamide (0.05 ml) were added to a solution of1-(4-methoxybenzyl)-4(N-methyl-N-phenylcarbamoyl)-1,2,3-triazole-5-carboxylicacid obtained in the preceding step (b) in methylene chloride (5 ml),and the mixture was stirred at 0° C. for 15 minutes and at roomtemperature for further 45 minutes.

The solvent was removed under reduced pressure, and the residue was onceconcentrated to dryness and then dissolved again in methylene chloride(5 ml). After the reaction mixture was cooled to 0° C., aluminumchloride (211 mg, 1.58 mmole) was added, and the mixture was stirred at0° C. for 3 hours. The reaction mixture was quenched with water, and theorganic materials were extracted with chloroform and washed with asaturated aqueous saline. The organic layer was dried over anhydrousmagnesium sulfate, and the solvent was removed under reduced pressure.Anisole and trifluoroacetic acid were added to the residue thusobtained, and the mixture was stirred at 60° C. for 2 hours. Thereaction solvent was removed under reduced pressure, and the resultingprecipitates were collected by filtration, washed with ethyl acetate,and desiccated to give the title compound,5-methyl-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c! 1!benzazepine as ayellow crystalline powder, which was the same as the title compound inExample 9.

Example 50

7-(2-methoxycarbonyl-2-methyl-(E)-ethenyl-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c!1!benzazepine

(a) 7-formyl-3-(4-methoxybenzyl)-4(5H),10-dioxo-3H-1,2,3-triazolo 5,4-c!1!benzazepine obtained in Example 11 (e-1: LP) (193 mg, 0.533 mmole) wassuspended in toluene (40 ml), and the mixture was added to methyl2-triphenylphosphoranylidene propionate (239 mg, 0.686 mmole) was added.After the reaction mixture was stirred at 70° C. for 3 hours, thesolvent was removed under reduced pressure. The resulting precipitateswere collected by filtration, washed with diethyl ether, and desiccatedto give3-(4-methoxybenzyl)-7-(2-methoxycarbonyl-2-methyl-(E)-ethenyl)-4(5H),10-dioxo-3H-1,2,3-triazolo5,4-c! 1!benzazepine (137 mg, 59.4%) as a yellow crystalline powder.

¹ H-NMR (DMSO-d₆): δ2.09 (3H, s), 3.72 (3H, s), 3.77 (3H, s), 6.08 (2H,s), 6.90 (2H, d), 7.31 (2H, d), 7.41 (1H, d), 7.57 (1H, s), 7.63 (1H,s), 8.25 (1H, d), 11.58 (1H, brs).

SIMS: m/z 433 (M⁺ +1).

(b) Anisole (1.25 ml) and trifluoroacetic acid (5 ml) were added to3-(4-methoxybenzyl)-7-(2-methoxycarbonyl-2-methyl-(E)-ethenyl)-4(5H),10-dioxo-3H-1,2,3-triazolo5,4-c! 1!benzazepine (137 mg, 0.317 mmole). After stirring at 65° C. for3 hours, the reaction solvent was removed under reduced pressure. Theresulting precipitates were collected by filtration, pulverized withdiethyl ether, and desiccated to give the title compound,7-(2-methoxycarbonyl-2-methyl-(E)-ethenyl-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine as a yellow crystalline powder (96 mg, 97%).

¹ H-NMR (DMSO-d₆): δ2.10 (3H, s), 3.78 (3H, s), 7.40 (1H, d), 7.57 (1H,s), 7.67 (1H, s), 8.31 (1H, d), 11.49 (1H, brs).

SIMS: m/z 313 (M⁺ +1).

Example 51

7-(2-(4-methoxybenzoyl)-(E)-ethenyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine

The following compounds were obtained in the same reactions andpost-treatments as in Example 50, except that methyl2-triphenylphophoranylidenepropionate was replaced bytriphenylphosphoranylidene-(4-methoxyacetophenone). (a)7-(2-(4-methoxybenzoyl)-(E)-ethenyl-3-(4-methoxybenzyl)-4(5H),10-dioxo-3H-1,2,3-triazolo5,4-c! 1!benzazepine, a yellow crystalline powder (194 mg, 74.9%);

¹ H-NMR (DMSO-d₆): δ3.72 (3H, s), 3.88 (3H, s), 6.09 (2H, s), 6.91 (2H,d), 7.12 (2H, d), 7.32 (2H, d), 7.62 (1H, d), 7.81 (1H, s), 7.95 (1H,d), 8.04 (1H, d), 8.17 (2H, d), 8.28 (1H, d), 11.52 (1H, brs).

FDMS: m/z 494 (M⁺ +1).

(b) the title compound,7-(2-(4-methoxybenzoyl)-(E)-ethenyl)-4(5H),10-dioxo-3H-1,2,3-triazolo5,4-c! 1!benzazepine, a yellow crystalline powder (149 mg, quant.);

¹ H-NMR (DMSO-d₆): δ3.88 (3H, s), 7.11 (2H, d), 7.62 (1H, d), 7.85 (1H,s), 7.92 (1H, d), 8.02 (1H, d), 8.16 (2H, d), 8.33 (1H, d), 11.40 (1H,brs).

FDMS: m/z 374 (M⁺ +1).

Example 52

7-(2-(N-(2-dimethylaminoethyl)carbamoyl-(E)-ethenyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine

(a) 7-formyl-1-(4-methoxybenzyl)-4(5H), 10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine (498 mg, 1.37 mmole) obtained in Example 11 (e-2:MP) was suspended in toluene (100 ml), and tert-butyltriphenylphosphoranylideneacetate (622 mg, 1.65 mmole) was added. Afterstirring at 70° C. for 3 hours, the reaction solvent was removed underreduced pressure. The resulting precipitates were collected byfiltration, pulverized with diethyl ether, and desiccated to give7-(2-(tert-butoxycarbonyl)-(E)-ethenyl)-1-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4, 5-c! 1!benzazepine as a yellow crystalline powder (426 mg, 67.5% ).

¹ H-NMR (DMSO-d₆): δ1.50 (9H, s), 3.71 (3H, s), 5.99 (2H, s), 6.61 (1H,d), 6.90 (2H, d), 7.20 (2H, d), 7.49 (1H, d), 7.65 (1H, d), 7.71 (1H,s), 8.16 (1H, d), 11.31 (1H, brs).

SIMS: m/z 461 (M⁺ +1).

(b) Trifluoroacetic acid (40 ml) was added to7-(2-(tert-butoxycarbonyl)-(E)-ethenyl)-1-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c! 1!benzazepine (426 mg, 0.925 mmole)obtained in the preceding step (a). After stirring at room temperaturefor 1 minute, the reaction solvent was removed under reduced pressure.The resulting precipitates were collected by filtration, pulverized withdiethyl ether, and desiccated to give7-(2-(carboxy-(E)-ethenyl)-1-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine as a yellow crystalline powder (362 mg, 96.8%).

¹ H-NMR (DMSO-d₆): δ3.71 (3H, s), 5.99 (2H, s), 6.62 (1H, d), 6.90 (2H,d), 7.29 (2H, d), 7.52 (1H, d), 7.64 (1H, d), 7.72 (1H, s), 8.17 (1H,d), 11.35 (1H, brs), 12.75 (1H, brs).

SIMS: m/z 405 (M⁺ +1).

(c) To a solution of7-(2-(carboxy-(E)-ethenyl)-1-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine (99 mg, 0.245 mmole) obtained in the preceding step(b) in N,N-dimethylformamide (10 ml) were added 1-hydroxybenzotriazole(67 mg, 0.496 mmole), N-methylmorpholine (33 μl, 0.300 mmole),1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (59 mg,0.308 mmole) and N,N-dimethylethylenediamine (41 μl, 0.373 mmole). Afterstirring at room temperature for 12 hours, the reaction solvent wasremoved under reduced pressure. The resulting precipitates werecollected by filtration, washed with ethyl acetate and water, anddesiccated to give1-(4-methoxybenzyl)-7-(2-(N-(2-dimethylaminoethyl)carbamoyl)-(E)-ethenyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine as a yellow crystalline powder (37 mg, 31.8%).

¹ H-NMR (DMSO-d₆): δ2.76 (6H, s), 3.20-3.30 (2H, m), 3.50-3.60 (2H, m),3.71 (3H, s), 5.99 (2H, s), 6.74(1H, d), 6.90 (2H, d), 7.29 (2H, d),7.42 (1H, d), 7.51 (1H, d), 7.66 (1H, s), 8.20 (1H, d), 8.67 (1H, brs),11.44 (1H, brs).

SIMS: m/z 475 (M⁺ +1).

(d) To1-(4-methoxybenzyl)-7-(2-(N-(2-dimethylaminoethyl)carbamoyl)-(E)-ethenyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine (37 mg, 0.0780 mmole) obtained in the precedingstep (c) were added anisole (0.25 ml) and trifluoroacetic acid (1 ml).After stirring at 70° C. for 10 minutes, the reaction solvent wasremoved under reduced pressure. The resulting precipitates werecollected by filtration, pulverized with diethyl ether, and desiccatedto give the trifluoroacetate salt of the title compound,7-(2-(N-(2-dimethylamino-ethyl)carbamoyl)-(E)-ethenyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine as a yellow crystalline powder (25 mg, 68.5%).

¹ H-NMR (DMSO-d₆): δ2.84(6H, s), 3.20-3.30 (2H, m), 3.50-3.60 (2H, m),6.71 (1H, d), 7.42 (1H, d), 7.53 (1H, d), 7.68 (1H, s), 8.32 (1H, d),8.58 (1H, t), 11.40 (1H, brs).

Example 53

7-(2-(N-benzylcarbamoyl)-(E)-ethenyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine

Starting from7-(2-carboxy-(E)-ethenyl)-1-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine obtained in Example 52 (b), the following compoundswere obtained by the reactions and post-treatments in the same manner asin Example 52, except that N,N-dimethylethylenediamine is replaced bybenzylamine.

(a)7-(2-(N-benzylcarbamoyl)-(E)-ethenyl)-1-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine, yellow crystalline powder;

¹ H-NMR (DMSO-d₆): δ3.71 (3H, s), 4.42 (2H, d), 6.00 (2H, s), 6.81 (1H,d), 6.90 (2H, d), 7.20-7.40 (2H, m), 7.43 (1H, d), 7.49 (1H, d), 7.66(1H, s), 8.20 (1H, d), 8.84(1H, t), 11.42 (1H, brs).

SIMS: m/z 494 (M⁺ +1).

(b) the title compound,7-(2-(N-benzylcarbamoyl)-(E)-ethenyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine, yellow crystalline powder (20 mg, 46.1% in twosteps);

¹ H-NMR (DMSO-d₆): δ4.42 (2H, d), 6.82 (1H, d), 7.20-7.40 (5H, m), 7.44(1H, d), 7.53 (1H, d), 7.70 (1H, s), 8.32 (1H, d), 8.83 (1H, t), 11.46(1H, brs).

Example 54

4(5H),10-dioxo-7-(2-(N-(2-pyridylmethyl)carbamoyl)-(E)-ethenyl)-1H-1,2,3-triazolo4,5-c! 1!benzazepine

Starting from7-(2-carboxy-(E)-ethenyl)-1-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine obtained in Example 52 (b), the following compoundswere obtained by the reactions and post-treatments in the same manner asin Example 52, except that N,N-dimethylethylenediamine is replaced by(2-pyridyl)methylamine.

(a)1-(4-methoxybenzyl)-4(5H),10-dioxo-7-(2-(N-(2-pyridylmethyl)carbamoyl)-(E)-ethenyl)-1H-1,2,3-triazolo4,5-c! 1!benzazepine, yellow crystalline powder (110 mg, 84.9%);

¹ H-NMR (DMSO-d₆): δ3.71 (3H, s), 4.51 (2H, d), 6.00 (2H, s), 6.87 (1H,d), 6.90 (2H, d), 7.20-7.40 (2H, m), 7.29 (2H, d), 7.43 (1H, d), 7.51(1H, d), 7.67 (1H, s), 7.77 (1H, dd), 8.20 (1H, d), 8.52 (1H, d), 8.92(1H, t), 11.41 (1H, s).

(b) the trifluoroacetic acid salt of the title compound,4(5H),10-dioxo-7-(2-(N-(2-pyridylmethyl)carbamoyl)-(E)-ethenyl)-1H-1,2,3-triazolo4,5-c! 1!benzazepine, yellow crystalline powder (92 mg, 96.1%);

¹ H-NMR (DMSO-d₆): δ4.60 (2H, d), 6.86 (1H, d), 7.45 (1H, d), 7.40-7.60(3H, m), 7.71 (1H, s), 8.04 (1H, t), 8.33 (1H, d), 8.64 (1H, d), 9.04(1H, t), 11.50 (1H, brs).

SIMS: m/z 375 (M⁺ -CF₃ CO₂ H).

Example 55

7-(N-(4(4-methyl-1-piperazinyl)methylbenzyl)carbamoyl-(E)-ethenyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine

(a) Under the argon atmosphere, 4-methylpiperazine (2.00 g, 20.0 mmole)and potassium carbonate (3.41 g, 24.7 mole ) were added to a solution of4-cyanobenzyl bromide (3.20 g, 16.3 mole) in tetrahydrofuran (30 ml).After stirring at room temperature for 18 hours, the mixture was dilutedwith water and extracted with ethyl acetate. The organic layer waswashed with water followed by a saturated aqueous saline, and dried overanhydrous magnesium sulfate. The solvent was removed under reducedpressure to give 4(4-methyl-1-piperazinylmethyl)benzonitrile as acolorless crystalline powder (1.49 g, 42.4%).

¹ H-NMR (CDCl₃): δ2.20-2.70 (4H, m), 2.29 (3H, s), 3.55 (2H, s), 7.45(2H, d), 7.60 (2H, d).

SIMS: m/z 215 (M⁺ +1).

(b) Under the argon atmosphere, a solution of4-(4-methyl-1-piperazinylmethyl)benzonitrile (511 mg, 2.37 mmole)obtained in the preceding step (a) in tetrahydrofuran (4 ml) was addedto the suspension of lithium aluminum hydride (170 mg, 4.48 mmole) intetrahydrofuran (10 ml) in an ice-bath. After stirring at roomtemperature for 19.5 hours, water (2 ml) and a 5N aqueous sodiumhydroxide solution (1 ml) were added in this sequence under ice-cooling,and the mixture was further stirred at room temperature for 30 minutes.Anhydrous magnesium sulfate was added, and the resulting mixture wasfiltered through celite. The solvent was removed under reduced pressureto give 4-(4-methyl-1-piperazinylmethyl)benzylamine as a colorless oil(491 mg, 94.5%).

¹ H-NMR (CDCl₃): δ2.20-2.70 (4H, m), 2.28 (3H, s), 3.49 (2H, s), 3.85(2H, s), 7.20-7.30 (4H, m).

SIMS: m/z 220 (M⁺ +1).

Starting from7-(2-carboxy-(E)-ethenyl)-1-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine obtained in Example 52 (b), the following compoundswere obtained by the reactions and post-treatments in the same manner asin Example 52, except that N,N-dimethylethylenediamine is replaced by4(4-methyl-1-piperazinylmethyl)benzylamine obtained in the precedingstep (b).

(c)1-(4-methoxybenzyl)-7-(N-(4-(4-methyl-1-piperazinyl)methylbenzyl)carbamoyl-(E)-ethenyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine, yellow crystalline powder (57 mg, 75.9%);

¹ H-NMR (DMSO-d₆): δ2.28 (3H, s), 3.20-3.70 (4H, m), 3.45 (2H, s), 3.71(3H, s), 4.40 (2H, d), 6.00 (2H, s), 6.81 (1H, d), 6.90 (2H, d),7.20-7.30 (4H, m), 7.29 (2H, d), 7.42 (1H, d), 7.49 (1H, d), 7.66 (1H,s), 8.20 (1H, d), 8.83 (1H, t), 11.42 (1H, brs).

SIMS: m/z 606 (M⁺ +1).

(d) the trifluoroacetic acid salt of the title compound,7-(N-(4-(4-methyl-1-piperazinylmethyl)benzyl)carbamoyl-(E)-ethenyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine, yellow crystalline powder (54 mg, 80.6%);

¹ H-NMR (DMSO-d₆): δ2.77 (3H, s), 3.70 (3/2H, s), 3.72 (3/2H, s), 4.43(2H, d), 6.83 (1H, d), 7.20-7.40 (4H, m), 7.44(1H, d), 7.53 (1H, d),7.70 (1H, s), 8.33 (1H, d), 8.87 (1H, t), 11.48 (1H, brs).

SIMS: m/z 486 (M⁺ -2CF₃ CO₂ H+1).

Example 56

4(5H),10-dioxo-7-(2-(N-(1H-tetrazol-5-yl)carbamoyl)-(E)-ethenyl)-1H-1,2,3-triazolo4,5-c! 1!benzazepine

(a) To a solution of7-(2-(carboxy-(E)-ethenyl)-1-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine (247 mg, 0.611 mmole) obtained in Example 52 (b) inN,N-dimethylformamide (25 ml) were added tributylamine (0.16 ml, 0.672mmole) and 2-chloro-1-methylpyridinium p-toluenesulfonate (204 mg, 0.680mmole) at room temperature. After stirring for 1 hour,3,4-dihyro-2H-pyrido 1,2-a!pyrimidine-2-one (115 mg, 0.776 mmole) and5-amino-1H-tetrazole (88 mg, 1.03 mmole). After stirring for further 60minutes at room temperature, the solvent was removed under reducedpressure. The resulting precipitates were collected by filtration,washed with water, ethyl acetate, methanol and water, and desiccated togive1-(4-methoxybenzyl)-4(5H),10-dioxo-7-(2-(N-(1H-tetrazol-5-yl)carbamoyl)-(E)-ethenyl)-1H-1,2,3-triazolo4,5-c! 1!benzazepine as a yellow crystalline powder (207 mg, 71.9%).

¹ H-NMR (DMSO-d₆): δ3.72 (3H, s), 6.00 (2H, s), 6.91 (2H, d), 6.99 (1H,d), 7.30 (2H, d), 7.55 (1H, d), 7.70 (1H, d), 7.76 (1H, s), 8.24 (1H,d), 11.47 (1H, brs), 12.42 (1H, brs).

SIMS: m/z 472 (M⁺ +1).

(b) To1-(4-methoxybenzyl)-4(5H),10-dioxo-7-(2-(N-(1H-tetrazol-5-yl)carbamoyl)-(E)-ethenyl)-1H-1,2,3-triazolo4,5-c! 1!benzazepine (207 mg, 0.439 mmole) obtained in the precedingstep (a) were added anisole (1.5 ml) and trifluoroacetic acid (6 ml).After stirring at 70° C. for 10 minutes, the solvent was removed underreduced pressure. The resulting precipitates were collected byfiltration, pulverized with diethyl ether, and desiccated. Thecrystalline powder thus obtained was purified with DIAION HP-20 (eluent,water) to give the disodium salt of the title compound,4(5H),10-dioxo-7-(2-(N-(1H-tetrazol-5-yl)carbamoyl)-(E)-ethenyl)-1H-1,2,3-triazolo4,5-c! 1!benzazepine as a pale yellow powder (122 mg, 72.0%).

¹ H-NMR (DMSO-d₆): δ7.00 (1H, d), 7.41 (1H, d), 7.49 (1H, d), 7.65 (1H,s), 8.31 (1H, d), 10.71 (2H, brs).

FDMS: m/z 351 (M⁺ -2Na).

Example 57

7-(hydroxyimino)methyl-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine

To a solution of 7-formyl-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine (121 mg, 0.5 mmole) obtained in Example 11 (f) inN,N-dimethylformamide (2.5 ml) were added hydroxylamine hydrochloride(42 mg, 0.6 mmole) and pyridine (1.0 ml), and the mixture was stirred atroom temperature for 16 hours. A 1N aqueous hydrochloric acid solution(2 ml) and diethyl ether (100 ml) were added to the reaction mixture.The resulting precipitates were collected by filtration, washed withwater and diethyl ether, and desiccated to give7-(hydroxyimino)methyl-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine as a yellow crystalline powder (110 mg, 86%).

¹ H-NMR (DMSO-d₆): δ7.52 (1H, dd), 7.78 (1H, d), 8.18 (1H, s), 8.30 (1H,d), 11.48 (1H, s), 11.81 (1H, s).

FDMS: m/z 257 (M⁺).

Example 58

7-(methoxyimino)methyl-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine

The title compound,7-(methoxyimino)methyl-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine was prepared as a yellow crystalline powder (120 mg, 89%)by the reactions and post-treatments in the same manner as in Example57, except that hydroxylamine hydrochloride was replaced byO-methylhydroxylamine hydrochloride.

¹ H-NMR (DMSO-d₆): δ3.97 (3H, s), 7.53 (1H, dd), 7.78 (1H, d), 8.28 (1H,s), 8.31 (1H, d), 11.46 (1H, brs).

FDMS: m/z 272 (M⁺ +1).

Example 59

7-(benzyloxyimino)methyl-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine

The title compound,7-(benzyloxyimino)methyl-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine was prepared as a yellow crystalline powder (94 mg, 90%)by the reactions and post-treatments in the same manner as in Example57, except that hydroxylamine hydrochloride was replaced byO-benzylhydroxylamine hydrochloride.

¹ H-NMR (DMSO-d₆): δ4.51-5.24 (2H, m), 7.34-7.81 (8H, m), 8.30-8.36 (2H,m), 8.58 (1H, brs).

FDMS: m/z 347 (M⁺).

Example 60

4(5H),10-dioxo-7-(N-propylamino)methyl-1H-1,2,3-triazolo 4,5-c!1!benzazepine

(a) To a solution of ethyl1-(4-methoxybenzyl)-4-(4-dimethoxymethyl-2-nitrobenzoyl)-1,2,3-triazole-5-carboxylate(7.26 g, 15 mmole) obtained in Example 11 (b-1: LP) in tetrahydrofuran(50 ml) was added a 1N aqueous hydrochloric acid solution (30 ml), andthe mixture was stirred at room temperature for 16 hours. The reactionmixture was extracted with ethyl acetate, and the organic layer waswashed with a saturated aqueous sodium hydrogen carbonate solution. Thesolvent was removed under reduced pressure to give ethyl4-(4-formyl-2-nitrobenzoyl)-1-(4-methoxybenzyl)1,2,3-triazole-5-carboxylateas a yellow crystalline powder (6.2 g, 94%).

¹ H-NMR (CDCl₃): δ1.39 (3H, t), 3.79 (3H, s), 4.45 (2H, q), 5.74 (2H,s), 6.85-6.87 (2H, m), 7.24-7.26 (2H, m), 7.77 (1H, d), 8.28 (1H, dd),8.68 (1H, d), 10.17 (1H, s).

FDMS: m/z 438 (M⁺).

(b) To a solution of ethyl4-(4-formyl-2-nitrobenzoyl)-1-(4-methoxybenzyl)1,2,3-triazole-5-carboxylateobtained in the preceding step (a) (415 mg, 0.95 mmole) in ethyl acetate(20 ml) were added propylamine (0.16 ml, 1.9 mmole) and 10% palladium oncarbon (150 mg), and the mixture was stirred under the hydrogenatmosphere at room temperature for 16 hours. The reaction mixture wasfiltered through celite, and the filtrate was removed under reducedpressure to give ethyl4-(2-amino-4(N-propylamino)-methylbenzoyl)-1-(4-methoxybenzyl)1,2,3-triazole-5-carboxylateas a yellow oil (440 mg, 98%).

¹ H-NMR (CDCl₃): δ0.92 (3H, t), 1.07 (3H, t), 1.49-1.55 (2H, m), 2.57(2H, t), 3.71 (2H, s), 3.80 (3H, s), 4.17 (2H, q), 5.85 (2H, s), 6.38(1H, brs), 6.49-6.68 (2H, m), 6.86-6.88 (2H, m), 7.34-7.36 (3H, m).

SIMS: m/z 452 (M⁺ +1).

(c) To a solution of ethyl4-(2-amino-4(N-propylamino)methylbenzoyl)-1-(4-methoxybenzyl)1,2,3-triazole-5-carboxylate(424 mg, 0.94 mmole) obtained in the preceding step (b) in methanol (1.2ml) was added a 28% methanolic sodium methoxide solution (0.26 ml, 1.06mmole), and the mixture was stirred at room temperature for 16 hours.The reaction mixture was diluted with diethyl ether. The resultingprecipitates were collected by filtration, washed with diethyl ether,and desiccated to give3-(4-methoxybenzyl)-4(5H),10-dioxo-7-(N-propylamino)methyl-3H-1,2,3-triazolo5,4-c! 1!benzazepine as a yellow crystalline powder (290 mg, 76%).

¹ H-NMR (DMSO-d₆): δ0.87 (3H, t), 1.42-1.47 (2H, m), 2.44-2.50 (2H, m),3.72-3.75 (6H, m), 6.07 (2H, s), 6.90 (2H, d), 7.30 (2H, d), 7.32 (1H,d), 7.49 (1H, s), 8.17 (1H, d).

SIMS: m/z 406 (M⁺ +1).

(d) To3-(4-methoxybenzyl)-4(5H),10-dioxo-7-(N-propylamino)methyl-3H-1,2,3-triazolo5,4-c! 1!benzazepine obtained in the preceding step (c) (130 mg, 0.32mmole) were added anisole (1 ml) and trifluoroacetic acid (10 ml), andthe mixture was stirred at 70° C. for 3 hours. The reaction mixture wasdiluted with diethyl ether. The resulting precipitates were collected byfiltration, washed with diethyl ether, and desiccated to give the titlecompound, 4(5H),10-dioxo-7-(N-propylamino)methyl-1H-1,2,3-triazolo4,5-c! 1!benzazepine as a yellow crystalline powder (77 mg, 84%).

¹ H-NMR (DMSO-d₆): δ0.91-0.94 (3H, m), 1.64-1.65 (2H, m), 2.80-2.90 (2H,m), 4.10 (2H, s), 7.25 (1H, d), 7.41 (1H, s), 8.25 (1H, d), 10.68 (1H,brs).

SIMS: m/z 286 (M⁺ +1).

Example 61

7-(N-acetyl-N-propylamino)methyl-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine

(a) To a solution of3-(4-methoxybenzyl)-4(5H),10-dioxo-7-(N-propylamino)methyl-3H-1,2,3-triazolo5,4-c! 1!benzazepine (142 mg, 0.35 mmole) obtained in Example 60 (c) inN,N-dimethylformamide (3.0 ml) were added acetyl chloride (0.12 ml, 1.75mmole) and triethylamine (0.24 ml, 1.75 mmole), and the mixture wasstirred at room temperature for 16 hours. The reaction mixture wasdiluted with diethyl ether (100 ml), and the resulting precipitates werecollected by filtration, washed with water and diethyl ether, anddesiccated to give7(N-acetyl-N-propylamino)methyl-3,4-methoxybenzyl-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine as a yellow crystalline powder (80 mg, 51%).

¹ H-NMR (DMSO-d₆): δ0.80-0.86 (3H, m), 1.46-1.57 (2H, m), 2.09-2.13 (3H,m), 3.21-3.28 (2H, m), 3.72 (3H, s), 4.55-4.64 (2H, m), 6.89-6.92 (2H,m), 7.17-7.43 (4H, m), 8.16-8.23 (1H, m), 11.43-11.52 (1H, m).

SIMS: m/z 448 (M⁺ +1).

(b) To7-(N-acetyl-N-propylamino)methyl-3-(4-methoxybenzyl-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine (75 mg, 0.16 mmole) obtained in the preceding step(a) were added anisole (1 ml) and trifluoroacetic acid (10 ml), and themixture was stirred at 70° C. for 3 hours. The reaction mixture wasdiluted with diethyl ether. The resulting precipitates were collected byfiltration, washed with diethyl ether, and desiccated to give the titlecompound,7-(N-acetyl-N-propylamino)methyl-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine as a yellow crystalline powder (32 mg, 61%).

¹ H-NMR (DMSO-d₆): δ0.80-0.87 (3H, m), 1.44-1.58 (2H, m), 1.99-2.14 (3H,m), 3.21-3.26 (2H, m), 4.56-4.65 (2H, m), 7.15-7.47 (2H, m), 8.23-8.30(1H, m), 11.35-11.45 (1H, m).

SIMS: m/z 328 (M⁺ +1).

Example 62

7-(N-(3-carboxypropanoyl)-N-propylaminomethyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine

(a) To a solution of3-(4-methoxybenzyl)-4(5H),10-dioxo-7-(N-propylamino)methyl-3H-1,2,3-triazolo5,4-c! 1!benzazepine (142 mg, 0.35 mmole) obtained in Example 60 (c) inN,N-dimethylformamide (4.0 ml) were added succinic anhydride (40 mg, 0.4mmole) and pyridine (0.065 ml, 0.8 mmole), and the mixture was stirredat room temperature for 16 hours. The reaction mixture was diluted witha 1N aqueous hydrochloric acid (2 ml) and diethyl ether (100 ml), andthe resulting precipitates were collected by filtration, washed withwater and diethyl ether, and desiccated to give7-(N-(3-carboxypropanoyl)-N-propylamino)methyl-3-(4-methoxybenzyl-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine as a yellow crys Dliu powder (80 mg, 51%).

¹ H-NMR (DMSO-d₆): δ0.78-0.87 (3H, m), 1.44-1.59 (2H, m), 2.33-2.47 (2H,m), 2.66-2.89 (2H, m), 3.22-3.39 (2H, m), 3.71 (3H, s), 4.56-4.68 (2H,m), 6.07 (2H, s), 6.89-6.92 (2H, m), 7.16-7.41 (4H, m), 8.13-8.23 (1H,m), 11.43-11.52 (1H, m), 12.05 (1H, brs).

SIMS: m/z 506 (M⁺ +1).

(b) To7-(N-(3-carboxypropanoyl)-N-propylamino)methyl-3-(4-methoxybenzyl-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine (160 mg, 0.32 mmole) obtained in the preceding step(a) were added anisole (1 ml) and trifluoroacetic acid (10 ml), and themixture was stirred at 70° C. for 3 hours. The reaction mixture wasdiluted with diethyl ether. The resulting precipitates were collected byfiltration, washed with diethyl ether, desiccated, dissolved in a 1Naqueous sodium hydroxide solution, and purified on DIAION HP-20(water:acetone=9:1) to give the sodium salt of the title compound,7-(N-(3-carboxypropanoyl)-N-propylamino)methyl-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine as a yellow crystalline powder (90 mg, 70%).

¹ H-NMR (D₂ O): δ0.85-0.94(3H, m), 1.53-1.66 (2H, m), 2.39-2.52 (3H, m),2.74-2.78 (1H, m), 3.27-3.37 (2H, m), 4.40-4.52 (2H, m), 6.90-6.94(2H,m), 8.08 (1H, m). SIMS: m/z 386 (M⁺ +1-Na).

Example 63

7-(N-benzylamino)methyl-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine

The following compounds were prepared by the reactions andpost-treatments in the same manner as in Example 60, except thatpropylamine was replaced by benzylamine.

(a) Ethyl4-(2-amino-4-(N-benzylamino)methylbenzoyl)-1-(4-methoxybenzyl)-1,2,3-triazole-5-carboxylate,a yellow oil (1.43 g, 95%).

¹ H-NMR (CDCl₃): δ1.07-1.10 (3H, m), 3.60-3.81 (7H, m), 4.11-4.20 (2H,m), 5.83-5.86 (2H, m), 6.26-6.40 (2H, brs), 6.50-6.73 (2H, m), 6.83-6.89(2H, m), 7.26-7.28 (3H, m), 7.31-7.40 (5H, m).

FDMS: m/z 499 (M⁺).

(b)7-(N-benzylamino)methyl-3-(4-methoxybenzyl)-4(5H),10-dioxo-3H-1,2,3-triazolo5,4-c! 1!benzazepine, a yellow crystalline powder (1.2 g, 97%);

¹ H-NMR (DMSO-d₆): δ3.63-3.73 (7H, m), 6.15 (2H, s), 6.85-6.88 (4H, m),7.09-7.12 (1H, m), 7.22-7.36 (6H, m), 8.00-8.02 (1H, m).

SIMS: m/z 454 (M⁺ +1).

(c) the title compound:7-(N-benzylamino)methyl-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine, a yellow crystalline powder (108 mg, 98%).

¹ H-NMR (DMSO-d₆): δ4.11-4.25 (4H, m), 7.16-7.61 (7H, m), 8.20-8.36 (1H,m), 9.54 (1H, brs), 11.50 (1H, brs).

SIMS: m/z 334(M⁺ +1).

Example 64

7-(N-acetyl-N-benzylaminomethyl)-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine

Starting from7-(N-benzylamino)methyl-3-(4-methoxybenzyl)-4(5H),10-dioxo-3H-1,2,3-triazolo5,4-c! 1!benzazepine, the following compounds were prepared by thereactions and post-treatments in the same manner as in Example 61.

(a)7-(N-acetyl-N-benzylaminomethyl)-3-(4-methoxybenzyl)-4(5H),10-dioxo-3H-1,2,3-triazolo5,4-c! 1!benzazepine, a yellow crystalline powder (140 mg, 81%);

¹ H-NMR (DMSO-d₆): δ2.10-2.17 (3H, m), 3.72 (7H, s), 4.50-4.58 (4H, m),6.08 (2H, s), 6.90-6.92 (2H, m), 7.16-7.47 (4H, m), 8.16-8.22 (1H, m),11.40-11.53 (1H, m).

SIMS: m/z 496 (M⁺ +1).

(b) the title compound:7-(N-acetyl-N-benzylaminomethyl)-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine, a yellow crystalline powder (85 mg, 70%).

¹ H-NMR (DMSO-d₆): δ2.11-2.18 (3H, m), 4.52-4.58 (4H, m), 7.15-7.52 (7H,m), 8.22-8.28 (1H, m), 11.33-11.41 (1H, m).

SIMS: m/z 375 (M⁺ +1).

Example 65

7-(N-(2-(N,N-dimethylamino)ethyl)aminomethyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine

The following compounds were prepared by the reactions andpost-treatments in the same manner as in Example 60, except thatpropylamine was replaced by N,N-dimethylethylenediamine.

(a) Ethyl4-(2-amino-4-(N-(2-(N,N-dimethylamino)ethyl)aminomethyl)benzoyl)-1-(4-methoxybenzyl)-1,2,3-triazole-5-carboxylate,a yellow oil (492 mg, 100%);

¹ H-NMR (CDCl₃): δ1.07 (3H, t), 2.20-2.25 (6H, m), 2.41-2.44(2H, m),2.65-2.68 (2H, m), 3.73-3.78 (2H, m), 3.80 (3H, s), 4.18 (2H, q), 5.85(2H, s), 6.39 (1H, brs), 6.52-6.88 (4H, m), 7.33-7.36 (3H, m).

FDMS: m/z 480 (M⁺).

(b)3-(4-methoxybenzyl)7-(N-(2-(N,N-dimethylamino)ethyl)aminomethyl)-4(5H),10-dioxo-3H-1,2,3-triazolo5,4-c! 1!benzazepine, a yellow crystalline powder (380 mg, 88%);

¹ H-NMR (DMSO-d₆): δ2.10 (6H, s), 2.30-2.33 (2H, m), 2.50-2.51 (2H, m),3.65-3.73 (5H, m), 6.15 (2H, s), 6.82-7.05 (4H, m), 7.27-7.30 (2H, m),7.98-8.01 (1H, m).

FDMS: m/z 434 (M⁺ +1).

(c) The di-trifluoroacetate of the title compound:7-(N-(2-(N,N-dimethylamino)ethyl)-aminomethyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine, a yellow crystalline powder (160 mg, 98%).

¹ H-NMR (D₂ O): δ3.06 (6H, s), 3.64-3.69 (4H, m), 4.71-4.77 (2H, m),7.36-7.39 (2H, m), 8.23-8.25 (1H, m).

SIMS: m/z 315 (M⁺ +1-2CF₃ CO₂ H).

Example 66

7-(N-(4-carboxybutyryl)aminomethyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine

The compounds shown in (a) and (b) below were prepared by the reactionsand post-treatments in the same manner as in Example 60, except thatpropylamine was replaced by 4-methoxybenzylamine.

(a) Ethyl4-(2-amino-4-(N-(4-methoxybenzyl)aminomethyl)benzoyl)-1-(4-methoxybenzyl)-1,2,3-triazole-5-carboxylate,a yellow oil (2.2 g, 100%);

¹ H-NMR (CDCl₃): δ1.07 (3H, t), 3.72 (4H, s), 3.78-3.81 (6H, m), 4.18(2H, q), 5.86 (2H, s), 6.40 (2H, brs), 6.52-6.71 (2H, m), 6.86-6.88 (4H,m), 7.23-7.25 (2H, m), 7.34-7.36 (3H, m).

FDMS: m/z 529 (M⁺).

(b)3-(4-methoxybenzyl)-7-(N-(4-methoxybenzyl)aminomethyl)-4(5H),10-dioxo-3H-1,2,3-triazolo5,4-c! 1!benzazepine, a yellow crystalline powder (1.73 g, 83%);

¹ H-NMR (DMSO-d₆): δ3.72 (3H, s), 3.76 (3H, s), 4.04-4.09 (4H, m), 6.08(2H, s), 6.90-6.98 (4H, m), 7.30-7.32 (2H, m), 7.43-7.52 (4H, m), 8.24(1H, d), 11.60 (1H, m).

SIMS: m/z 484 (M⁺ +1).

(c) The compounds shown below were prepared by the reactions andpost-treatments in the same manner as in Example 62, except that3-(4-methoxybenzyl)-7-(N-(4-methoxybenzyl)aminomethyl)-4(5H),10-dioxo-3H-1,2,3-triazolo5,4-c! 1!benzazepine was used and succunic anhydride was replaced byglutaric anhydride.

7-(N-(4-carboxybutyryl)-N-(4-methoxybenzyl)aminomethyl)-3-(4-methoxybenzyl)-4(5H),10-dioxo-3H-1,2,3-triazolo5,4-c! 1!benzazepine, a yellow crystalline powder (140 mg, 67%).

¹ H-NMR (DMSO-d₆): δ1.75-1.82 (2H, m), 2.22-2.53 (4H, m), 3.71-3.72 (6H,s), 4.45-4.54 (4H, m), 6.08 (2H, s), 6.86-6.93 (4H, m), 7.14-7.16 (3H,m), 7.30-7.42 (3H, m), 8.15-8.21 (1H, m), 11.50-11.55 (1H, m), 12.05(1H, brs).

SIMS: m/z 598 (M⁺ +1).

(d) The title compound:7-(N-(4-carboxybutyryl)aminomethyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine, a yellow crystalline powder (80 mg, 100%).

¹ H-NMR (DMSO-d₆): δ1.74-1.82 (2H, m), 2.21-2.35 (4H, m), 4.29-4.54 (2H,m), 7.11-7.21 (1H, m), 7.36 (1H, s), 8.21-8.24 (1H, m), 8.41-8.43 (1H,m), 10.98-11.17 (1H, m), 12.05 (1H, brs).

SIMS: m/z 358 (M⁺ +1).

Example 67

7-(N-acetylaminomethyl)-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine

The following compounds were prepared by the reactions andpost-treatments in the same manner as in Example 62, except that3-(4-methoxybenzyl)-7-(N-(4-methoxybenzyl)aminomethyl)-4(5H),10-dioxo-3H-1,2,3-triazolo5,4-c! 1!benzazepine obtained in Example 66 (b) was used and succinicanhydride was replaced by acetic anhydride.

(a)7-(N-acetyl-N-(4-methoxybenzyl)aminomethyl)-3-(4-methoxybenzyl)-4(5H),10-dioxo-3H-1,2,3-triazolo5,4-c! 1!benzazepine (283 mg, quant.).

¹ H-NMR (DMSO-d₆): δ2.07 (3/2H, s), 2.19 (3/2H, s), 3.718 (3H, s), 3.70(3/2H, s), 3.724 (3/2H, s), 4.42-4.55 (4H, m), 6.08 (2H, s), 6.84-6.94(3H, m), 7.14-7.18 (2H, m), 7.14-7.18 (2H, m), 7.28-7.35 (2H, m),7.33-7.35 (1/2H, m), 7.88-7.96 (1H, m), 8.14-8.22 (1H, m), 8.39-8.44(1/2H, m), 8.84-8.86 (1H, m), 11.46 (1/2H, s), 11.53 (1/2H, s).

(b) The title compound:7-(N-(acetylaminomethyl)-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine (23 mg, quant.).

¹ H-NMR (DMSO-d₆): δ1.93 (3H, s), 4.31 (2H, d), 7.21 (1H, d), 7.42 (1H,s), 8.25 (1H, d), 8.49 (1H, t), 11.43 (1H, brs).

Example 68

7-(N-methanesulfonylaminomethyl)-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine

(a) To a solution of3-(4-methoxybenzyl)-7-(N-(4-methoxybenzyl)aminomethyl)-4(5H),10-dioxo-3H-1,2,3-triazolo5,4-c! 1!benzazepine (193 mg, 0.4 mmole) obtained in Example 66 (b) inN,N-dimethylformamide (10 ml) were added methanesulfonyl chloride (37μl, 0.48 mmole) and triethylamine (67 μl, 0.48 mmole), and the mixturewas stirred at room temperature for 16 hours. The reaction mixture wasdiluted with diethyl ether. The resulting precipitates were collected byfiltration, washed with water and diethyl ether, and desiccated to give7-(N-methanesulfonyl-N-(4-methoxybenzyl)aminomethyl)-3-(4-methoxybenzyl)-4(5H),10-dioxo-3H-1,2,3-triazolo5,4-c! 1!benzazepine, a yellow crystalline powder (130 mg, 58%).

¹ H-NMR (DMSO-d₆): δ3.01(3H, s), 3.64 (3H, s), 3.72 (3H, s), 4.28 (2H,s), 4.33 (2H, s), 6.08 (2H, s), 6.82 (2H, d), 6.92 (2H, d), 7.16-7.21(3H, m), 7.25-7.33 (3H, m), 7.42 (1H, s), 8.13 (1H, d), 11.51 (1H, brs).

SIMS: m/z 562 (M⁺ +1).

(b) To7-(N-methanesulfonyl-N-(4-methoxybenzyl)aminomethyl)-3-(4-methoxybenzyl)-4(5H),10-dioxo-3H-1,2,3-triazolo5,4-c! 1!benzazepine (110 mg, 0.2 mmole) obtained in the preceding step(a) were added anisole (10 ml) and trifluoroacetic acid (1 ml), and themixture was stirred at 65° C. for 2 hours. The reaction mixture wasdiluted with diethyl ether. The resulting precipitates were collected byfiltration, washed with diethyl ether, and desiccated to give the titlecompound:7-(N-methanesulfonylaminomethyl)-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine as a yellow crystalline powder (60 mg, 93%).

¹ H-NMR (DMSO-d₆): δ2.95 (3H, s), 4.23-4.25 (2H, d), 7.30 (1H, d), 7.55(1H, s), 7.72-7.75 (1H, m), 8.28 (1H, d), 11.45 (1H, brs).

SIMS: m/z 322 (M⁺ +1).

Example 69

7-(N-benzenesulfonylaminomethyl)-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine

The following compounds were prepared by the reactions andpost-treatments in the same manner as in Example 68, except thatmethanesulfonyl chloride was replaced by benzenesulfonyl chloride.

(a)7-(N-benzenesulfonyl-N-(4-methoxybenzyl)aminomethyl)-3-(4-methoxybenzyl)-4(5H),10-dioxo-3H-1,2,3-triazolo5,4-c! 1!benzazepine, a yellow crystalline powder (130 mg, 58%);

¹ H-NMR (DMSO-d₆): δ3.55(3H, s), 3.72 (3H, s), 4.29 (2H, s), 4.30 (2H,s), 6.08 (2H, s), 6.68 (2H, d), 6.91 (2H, d), 7.00-7.03 (3H, m),7.31-7.33 (3H, m), 7.58-7.67 (3H, m), 7.87-8.03 (3H, m), 11.46 (1H,brs).

SIMS: m/z 624 (M⁺ +1).

(b) The title compound:7-(N-benzenesulfonylaminomethyl)-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine, a yellow crystalline powder (60 mg, 98%).

¹ H-NMR (DMSO-d₆): δ4.02-4.04(2H, m), 7.19 (1H, d), 7.50 (1H, s),7.56-7.65 (3H, m), 7.81-7.83 (2H, m), 8.19 (1H, d), 8.31-8.34 (1H, m),11.45 (1H, s).

SIMS: m/z 384 (M⁺).

Example 70

7-(N-(4-fluorobenzenesulfonyl)aminomethyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine

The following compounds were prepared by the reactions andpost-treatments in the same manner as in Example 68, except thatmethanesulfonyl chloride was replaced by 4-fluorobenzenesulfonylchloride.

(a)7-(N-(4-fluorobenzenesulfonyl)-N-(4-methoxybenzyl)aminomethyl)-3-(4-methoxybenzyl)-4(5H),10-dioxo-3H-1,2,3-triazolo5,4-c! 1!benzazepine, a yellow crystalline powder (150 mg, 67%);

¹ H-NMR (DMSO-d₆): δ3.55(2H, s), 3.72 (4H, s), 4.29 (2H, s), 4.32 (2H,s), 6.08 (2H, s), 6.68-6.70 (2H, m), 6.90-7.04 (5H, m), 7.31-7.33 (3H,m), 7.41-7.46 (2H, m), 7.92-7.96 (2H, m), 8.03-8.05 (1H, m), 11.47 (1H,brs).

SIMS: m/z 642 (M⁺ +1).

(b) The title compound:7-(N-(4-fluorobenzenesulfonyl)aminomethyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine, a yellow crystalline powder (50 mg, 62%).

¹ H-NMR (DMSO-d₆): δ4.04-4.06 (2H, m), 7.09-7.18 (1H, m), 7.32-7.47 (3H,m), 7.84-7.88 (2H, m), 8.19-8.21 (1H, m), 8.35-8.38 (1H, m), 11.41 (1H,brs).

SIMS: m/z 402 (M⁺ +1).

Example 71

7-(N-(4-chlorobenzenesulfonyl)aminomethyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine

The following compounds were prepared by the reactions andpost-treatments in the same manner as in Example 68, except thatmethanesulfonyl chloride was replaced by 4-chlorobenzenesulfonylchloride.

(a)7-(N-(4-chlorobenzenesulfonyl)-N-(4-methoxybenzyl)aminomethyl)-3-(4-methoxybenzyl)-4(5H),10-dioxo-3H-1,2,3-triazolo5,4-c! 1!benzazepine, a yellow crystalline powder (130 mg, 56%);

¹ H-NMR (DMSO-d₆): δ3.56(3H, s), 3.72 (3H, s), 4.31 (2H, s), 4.32 (2H,s), 6.08 (2H, s), 6.69 (2H, d), 6.91 (2H, d), 7.03-7.06 (3H, m),7.30-7.33 (3H, m), 7.63-7.65 (2H, m), 7.84-7.86 (2H, m), 8.02-8.05 (1H,m), 11.45 (1H, brs).

SIMS: m/z 658 (M⁺ +1).

(b) The title compound:7-(N-(4-chlorobenzenesulfonyl)aminomethyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine, a yellow crystalline powder (65 mg, 87%).

¹ H-NMR (DMSO-d₆): δ4.05-4.07 (2H, m), 7.18-7.20 (2H, m), 7.36-7.38 (1H,m), 7.43-7.62 (2H, m), 7.76-7.79 (2H, m), 8.18-8.20 (1H, m), 8.42-8.45(1H, m), 11.39 (1H, brs).

SIMS: m/z 417 (M⁺ +1).

Example 72

7-bis(4-methoxyphenyl)methyl-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine

To 7-formyl-4(5H),10-dioxo-1H-1,2,3-triazolo 5,4-c! 1!benzazepine (550mg, 1.5 mmole) obtained in Example 11 (f) were added anisole (1 ml) andtrifluoroacetic acid (10 ml), and the mixture was stirred at 70° C. for3 hours. The reaction mixture was diluted with diethyl ether. Theresulting precipitates were collected by filtration, and desiccated togive the title compound:7-bis(4-methoxyphenyl)methyl-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine as a yellow crystalline powder (610 mg, 92%).

¹ H-NMR (DMSO-d₆): δ3.70-3.73 (6H, m), 5.55-5.80 (1H, m), 6.75-7.09 (9H,m), 7.30-7.37 (1H, m), 8.20-8.23 (1H, m), 11.32 (1H, brs).

SIMS: m/z 440 (M⁺).

Example 73

7-(2-methoxyphenacyloxy)-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine

(a) To the solution of7-hydroxy-1-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine (150 mg, 0.428 mmole) obtained in Example 25 (e) in themixture of acetone (2 ml) and N,N-dimethylformamide (2 ml) were addedpotassium carbonate (71 mg, 0.514 mmole) and 2-methoxyphenacyl bromide(147 mg, 0.642 mmole), and the mixture was stirred at room temperaturefor 2 hours. The reaction mixture was diluted with water, and theresulting precipitates were collected by filtration, pulverized withdiethyl ether, and desiccated to give1-(4-methoxybenzyl)-7-(2-methoxyphenacyloxy)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine (155 mg, 73%).

¹ H-NMR (DMSO-d₆): δ3.71 (3H, s), 3.99 (3H, s), 5.45 (2H, s), 6.01 (2H,s), 6.90 (2H, d), 6.94 (1H, dd), 7.00 (1H, d), 7.11 (1H, dd), 7.27 (2H,d), 7.28 (1H, d), 7.66 (1H, ddd), 7.81 (1H, dd), 8.14 (1H, d), 11.20(1H, s).

SIMS: m/z 499 (M⁺ +1).

(b) To1-(4-methoxybenzyl)-7-(2-methoxyphenacyloxy)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine (194 mg, 0.389 mmole) obtained in the precedingstep (a) were added anisole (0.4 ml) and trifluoroacetic acid (4.0 ml),and the mixture was stirred at 60° C. for 3 hours. The solvent wasremoved under reduced pressure. The resulting precipitates werecollected by filtration, pulverized with diethyl ether, and desiccatedto give the title compound,7-(2-methoxyphenacyloxy)-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine as a pale yellow powder (134 mg, 91%).

¹ H-NMR (DMSO-d₆): δ4.00 (3H, s), 5.45 (2H, s), 6.94 (1H, dd), 7.04 (1H,d), 7.11 (1H, dd), 7.28 (1H, d), 7.66 (1H, ddd), 7.82 (1H, dd), 8.25(1H, d), 11.24 (1H, s).

SIMS: m/z 379 (M⁺ +1).

Example 74

7-(4-chlorophenacyloxy)-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine

(a) 7-hydroxy-1-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine (150 mg, 0.428 mmole) obtained in Example 25 (e)was dissolved in the mixture of acetone (2 ml) and N,N-dimethylformamide(2 ml), and potassium carbonate (71 mg, 0.514 mmole) and4-chlorophenacyl bromide (147 mg, 0.514 mmole) were added. The mixturewas subjected to the reaction and post-treatment in the same way as inExample 73 to give7-(4-chlorophenacyloxy)-1-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine (197 mg, 92%).

¹ H-NMR (DMSO-d₆): δ3.71 (3H, s), 5.74 (2H, s), 6.01 (2H, s), 6.90 (2H,d), 6.99 (1H, d), 7.02 (1H, s), 7.27 (2H, d), 7.69 (2H, d), 8.04 (2H,d), 8.15 (1H, d), 11.17 (1H, s).

EIMS: m/z 502 (M⁺).

(b)7-(4-chlorophenacyloxy)-1-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine (250 mg, 0.497 mmole) obtained in the precedingstep (a) was subjected to deprotection and post-treatment with anisole(0.5 ml) and trifluoroacetic acid (5.0 ml) according to Example 63 togive the title compound,7-(4-chlorophenacyloxy)-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine as a pale yellow powder (176 mg, 93%).

¹ H-NMR (DMSO-d₆): δ5.74 (2H, s), 7.02 (1H, dd), 7.07 (1H, d), 7.69 (1H,d), 8.04 (2H, d), 8.26 (1H, d), 11.21 (1H, s).

SIMS: m/z 383 (M⁺ +1).

Example 75

4(5H),10-dioxo-7-(3-phenoxypropoxy)-1H-1,2,3-triazolo 4,5-c!1!benzazepine

(a) 7-hydroxy-1-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine (300 mg, 0.856 mmole) obtained in Example 25 (e)was dissolved in the mixture of acetone (3 ml) and N,N-dimethylformamide(6 ml), and potassium carbonate (237 mg, 1.72 mmole) and 3-phenoxypropylbromide (0.67 ml, 4.25 mmole) were added. The mixture was subjected tothe reaction and post-treatment in the same way as in Example 73 to give1-(4-methoxybenzyl)-4(5H),10-dioxo-7-(3-phenoxypropoxy)-1H-1,2,3-triazolo 4,5-c! 1!benzazepine (178 mg, 43%).

¹ H-NMR (DMSO-d₆): δ2.15-2.26 (2H, m), 3.71 (3H, s), 4.13 (2H, t), 4.24(2H, t), 6.01 (2H, s), 6.86-7.05 (6H, m), 7.09 (1H, d), 7.23-7.35 (4H,m), 8.15 (1H, d), 11.22 (1H, s).

EIMS: m/z 484 (M⁺).

(b)1-(4-methoxybenzyl)-4(5H),10-dioxo-7-(3-phenoxypropoxy)-1H-1,2,3-triazolo4,5-c!1!benzazepine (202 mg, 0.417 mmole) obtained in the preceding step (a)was subjected to deprotection and post-treatment with anisole (0.4 ml)and trifluoroacetic acid (4.0 ml) according to Example 73 to give thetitle compound, 4(5H),10-dioxo-7-(3-phenoxy-propoxy)-1H-1,2,3-triazolo4,5-c! 1!benzazepine as a pale yellow powder (141 mg, 93%).

¹ H-NMR (DMSO-d₆): δ2.23 (2H, quintet), 4.14 (2H, t), 4.25 (2H, t),6.90-7.03 (4H, m), 7.13 (1H, d), 7.28 (2H, dd), 8.26 (1H, d), 11.26 (1H,s).

SIMS: m/z 365 (M⁺ +1).

Example 76

4(5H),10-dioxo-7-(3-phenylpropoxy)-1H-1,2,3-triazolo 4,5-c!1!benzazepine

(a) 7-hydroxy-1-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine (150 mg, 0.428 mmole) obtained in Example 25 (e)was dissolved in N,N-dimethylformamide (5 ml), and potassium carbonate(166 mg, 1.20 mmole) and 3-phenylpropyl.bromide (1.08 ml, 1.19 mmole)were added. The mixture was subjected to the reaction and post-treatmentin the same way as in Example 73 to give1-(4-methoxybenzyl)-4(5H),10-dioxo-7-(3-phenylpropoxy)-1H-1,2,3-triazolo4,5-c! 1!benzazepine (130 mg, 65%).

¹ H-NMR (DMSO-d₆): δ2.06 (2H, quintet), 3.33 (2H, t), 3.71 (3H, s), 4.06(2H, t), 6.01 (2H, s), 6.89 (2H, d), 6.92 (1H, dd), 7.06 (1H, d),7.15-7.33 (7H, m), 8.15 (1H, d), 11.22 (1H, s).

EIMS: m/z 468 (M⁺).

(b)1-(4-methoxybenzyl)-4(5H),10-dioxo-7-(3-phenylpropoxy)-1H-1,2,3-triazolo4,5-c! 1!benzazepine (114 mg, 0.243 mmole) obtained in the precedingstep (a) was subjected to deprotection and post-treatment with anisole(0.2 ml) and trifluoroacetic acid (2.0 ml) according to Example 73 togive the title compound,4(5H),10-dioxo-7-(3-phenylpropoxy)-1H-1,2,3-triazolo 4,5-c!1!benzazepine as a pale yellow powder (87 mg, 100%).

¹ H-NMR (DMSO-d₆): δ2.07 (2H, quintet), 3.41 (2H, t), 4.07 (2H, t), 6.95(1H, dd), 7.11 (1H, d), 7.16-7.35 (5H, m), 8.26 (1H, d), 11.25 (1H, s).

SIMS: m/z 349 (M⁺ +1).

Example 77

4(5H),10-dioxo-7-(4-phenylbutoxy)-1H-1,2,3-triazolo 4,5-c! 1!benzazepine

(a) 7-hydroxy-1-(4-methoxybenzyl)-4(5H), 10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine (200 mg, 0. 571 mmole) obtained in Example 25 (e)was dissolved in N,N-dimethylformamide (6 ml), and potassium carbonate(138 mg, 0.998 mmole) and 4-phenylbutyl bromide (243 mg, 1.14 mmole)were added. The mixture was subjected to the reaction and post-treatmentin the same way as in Example 73 to give 1-(4-methoxybenzyl)-4(5H),10-dioxo-7-(4-phenylbutoxy )-1H-1,2,3-triazolo 4, 5-c! 1!benzazepine(186 mg, 68%).

¹ H-NMR (DMSO-d₆): δ1.67-1.82 (4H, m), 2.64 (2H, t), 3.71 (3H, s), 4.09(2H, t), 6.01 (2H, s), 6.89 (2H, d), 6.91 (1H, dd), 7.05 (1H, d),7.15-7.35 (7H, m), 8.14 (1H, d), 11.21 (1H, s).

SIMS: m/z 483 (M⁺ +1).

(b)1-(4-methoxybenzyl)-4(5H),10-dioxo-7-(4-phenylbutoxy)-1H-1,2,3-triazolo4,5-c! 1!benzazepine (200 mg, 0.414 mmole) obtained in the precedingstep (a) was subjected to deprotection and post-treatment with anisole(0.4 ml) and trifluoroacetic acid (4.0 ml) according to Example 73 togive the title compound,4(5H),10-dioxo-7-(4-phenylbutoxy)-1H-1,2,3-triazolo 4,5-c! 1!benzazepineas a pale yellow powder (141 mg, 94%).

¹ H-NMR (DMSO-d₆): δ1.66-1.83 (4H, m), 2.65 (2H, t), 4.09 (2H, t), 6.94(1H, dd), 7.09 (1H, d), 7.15-7.32 (5H, m), 8.25 (1H, d), 11.25 (1H, s).

EIMS: m/z 362 (M⁺).

Example 78

4(5H),10-dioxo-7-(2-phenoxyethoxy)-1H-1,2,3-triazolo 4,5-c!1!benzazepine

(a) 7-hydroxy-1-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine (200 mg, 0.571 mmole) obtained in Example 25 (e)was dissolved in N,N-dimethylform-amide (7 ml), and potassium carbonate(118 mg, 0.854 mmole) and 1-iodo-2-phenoxy-ethane (354 mg, 1.43 mmole)were added. The mixture was subjected to the reaction and post-treatmentin the same way as in Example 73 to give1-(4-methoxybenzyl)-4(5H),10-dioxo-7-(2-phenoxyethoxy)-1H-1,2,3-triazolo4,5-c! 1!benzazepine (141 mg, 52%).

¹ H-NMR (DMSO-d₆): δ3.71 (3H, s), 4.31-4.38 (2H, m), 4.38-4.47 (2H, m),6.01 (2H, s), 6.90 (2H, d), 6.93-7.06 (4H, m), 7.10 (1H, d), 7.25-7.38(4H, m), 8.18 (1H, d), 11.26 (1H, 25 s).

SIMS: m/z 471 (M⁺ +1).

(b)1-(4-methoxybenzyl)-4(5H),10-dioxo-7-(2-phenoxyethoxy)-1H-1,2,3-triazolo4,5-c! 1!benzazepine (164 mg, 0.349 mmole) obtained in the precedingstep (a) was subjected to deprotection and post-treatment with anisole(0.3 ml) and trifluoroacetic acid (3.0 ml) according to Example 73 togive the title compound,4(5H),10-dioxo-7-(2-phenoxyethoxy)-1H-1,2,3-triazolo 4,5-c!1!benzazepine as a pale yellow powder (102 mg, 83%).

¹ H-NMR (DMSO-d₆): δ4.30-4.38 (2H, m), 4.38-4.50 (2H, m), 6.92-7.05 (2H,m), 7.03 (1H, dd), 7.15 (1H, d), 7.31 (2H, dd), 8.29 (1H, d), 11.27 (1H,s).

SIMS: m/z 351 (M⁺ +1).

Example 79

4(5H),10-dioxo-7-(2-oxo-4-phenylbutoxy)-1H-1,2,3-triazolo 4,5-c!1!benzazepine

(a) 7-hydroxy-1-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine (200 mg, 0.571 mmole) obtained in Example 25 (e)was dissolved in the mixture of acetone (3 ml) and N,N-dimethylformamide(3 ml), and potassium carbonate (95 mg, 0.687 mmole) and1-bromo-4-phenyl-2-butanone (156 mg, 0.687 mmole) were added. Themixture was subjected to the reaction and post-treatment in the same wayas in Example 73 to give1-(4-methoxybenzyl)-4(5H),10-dioxo-7-(2-oxo-4-phenylbutoxy)-1H-1,2,3-triazolo4,5-c! 1!benzazepine (267 mg, 94%).

¹ H-NMR (DMSO-d₆): δ2.80-2.92 (4H, m), 3.71 (3H, s), 4.98 (2H, s), 6.01(2H, s), 6.85 (1H, dd), 6.90 (2H, d), 6.95 (1H, d), 7.15-7.33 (7H, m),8.12 (1H, d), 11.18 (1H, s).

EIMS: m/z 496 (M⁺).

(b)1-(4-methoxybenzyl)-4(5H),10-dioxo-7-(2-oxo-4-phenylbutoxy)-1H-1,2,3-triazolo4,5-c! 1!benzazepine (267 mg, 0.538 mmole) obtained in the precedingstep (a) was subjected to deprotection and post-treatment with anisole(0.5 ml) and trifluoroacetic acid (5.0 ml) according to Example 73 togive the title compound,4(5H),10-dioxo-7-(2-oxo-4-phenylbutoxy)-1H-1,2,3-triazolo 4,5-c!1!benzazepine as a white powder (182 mg, 90%).

¹ H-NMR (DMSO-d₆): δ2.82-2.94 (4H, m), 4.99 (2H, s), 6.88 (1H, dd), 6.99(1H, d), 7.16-7.33 (5H, m), 8.32 (1H, d), 11.23 (1H, s).

SIMS: m/z 377 (M⁺ +1).

Example 80

7-(2-hydroxy-4-phenylbutoxy)-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine

7-(2-oxo-4-phenylbutoxy)-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine (38 mg, 0.101 mmole) obtained in Example 79 (b) wassuspended in methanol (1 ml), lithium borohydride (4 mg, 0.106 mmole)was added, and the mixture was stirred at room temperature overnight.N,N-dimethylformamide (0.2 ml) was then added, and stirring was furthercontinued overnight. The reaction mixture was diluted with water andthen acidified with hydrochloric acid. The resulting precipitates werecollected by filtration to give the title compound,7-(2-hydroxy-4-phenylbutoxy)-4,5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine (33 mg, 86%).

¹ H-NMR (DMSO-d₆): δ1.65-1.90 (2H, m), 2.58-2.91 (2H, m), 3.82 (1H, s),3.90-4.06 (2H, m), 5.11 (1H, s), 6.96 (1H, dd), 7.10 (1H, d),7.13-7.34(5H, m), 8.26 (1H, d), 11.25 (1H, s).

SIMS: m/z 379 (M⁺ +1).

Example 81

7-(3-(4-benzyl-1-piperazinyl)propoxy)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine

(a) 7-hydroxy-1-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine (500 mg, 1.43 mmole) obtained in Example 25 (e) wasdissolved in N,N-dimethylformamide (15 ml), and potassium carbonate (296mg, 2.14 mmole) and 1-chloro-3-iodopropane (0.31 ml, 2.89 mmole) wereadded. The mixture was subjected to the reaction and post-treatment inthe same way as in Example 73 to give7-(3-chloropropoxy)-1-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine (582 mg, 96%).

¹ H-NMR (DMSO-d₆): δ2.21 (2H, quintet), 3.71 (3H, s), 3.80 (2H, t), 4.19(2H, t), 6.01 (2H, s), 6.90 (2H, d), 6.94 (1H, dd), 7.09 (1H, d), 7.27(2H, d), 8.16 (1H, d), 11.22 (1H, s).

EIMS: m/z 426 (M⁺).

(b) To the solution of7-(3-chloropropoxy)-1-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine (100 mg, 0.234 mmol) obtained in the preceding step(a) in N,N-dimethylformamide (2 ml) were added potassium carbonate (162mg, 1.17 mmole), 4-benzylpiperazine (0.20 mmole, 1.15 mmole) and sodiumiodide (105 mg, 0.701 mmole), and the mixture was stirred at 60° C. for2 days. The reaction mixture was diluted with water, and the resultingprecipitates were collected by filtration to give7-(3-(4-benzyl-1-piperazinyl)propoxy)-1-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine (116 mg, 87%).

¹ H-NMR (DMSO-d₆): δ1.90 (2H, quintet), 2.20-2.55 (10H, m), 3.45 (2H,s), 3.71 (3H, s), 4.09 (2H, t), 6.01 (1H, s), 6.89 (2H, d), 6.90 (1H,dd), 7.05 (1H, d), 7.20-7.36 (7H, m), 8.14 (1H, d), 11.22 (1H, s).

EIMS: m/z 566 (M⁺).

(c)7-(3-(4-benzyl-1-piperazinyl)propoxy)-1-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine (164 mg, 0.289 mmole) obtained in the precedingstep (b) was subjected to deprotection and post-treatment with anisole(0.5 ml) and trifluoroacetic acid (5.0 ml) according to Example 73 togive the di-trifluoroacetatic acid salt of the title compound,7-(3-(4-benzyl-1-piperazinyl)propoxy)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine (148 mg, 76%).

¹ H-NMR (DMSO-d₆): δ2.25-2.37 (2H, m), 3.53-4.05 (12H, m), 4.45 (2H, s),6.22-6.32 (2H, m), 7.33-7.55 (5H, m), 7.62-7.72 (1H, m).

SIMS: m/z 447 (M⁺ +1-2CF₃ CO₂ H).

Example 82

4(5H),10-dioxo-7-(3-(1-piperidinyl)propoxy)-1H-1,2,3-triazolo 4,5-c!1!benzazepine

(a) To the solution of7-(3-chloropropoxy)-1-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine (100 mg, 0.234 mmole) obtained in Example 81 (a) inN,N-dimethylformamide (2 ml) were added potassium carbonate (162 mg,1.17 mmole), piperidine (0.12 ml, 1.21 mmole) and sodium iodide (105 mg,0.701 mmole). The reaction mixture was subjected to reaction andpost-treatment in the same manner as in Example 81 (b) to give1-(4-methoxybenzyl)-4(5H),10-dioxo-7-(3-(1-piperidinyl)propoxy)-1H-1,2,3-triazolo4,5-c! 1!benzazepine (94 mg, 84%).

¹ H-NMR (DMSO-d₆): δ1.30-1.43 (2H, m), 1.43-1.55 (4H, m), 1.89 (2H,quintet),2.25-2.42 (4H, m), 2.36 (2H, t), 3.71 (3H, s), 4.09 (2H, t),6.01 (1H, s), 6.87-6.95 (1H, m), 6.89 (2H, d), 7.05 (1H, d), 7.27 (2H,d), 8.14 (1H, d), 11.19 (1H, s).

EIMS: m/z 476 (M⁺ +1).

(b)1-(4-methoxybenzyl)-4(5H),10-dioxo-7-(3-(1-piperidinyl)propoxy)-1H-1,2,3-triazolo4,5-c! 1!benzazepine (132 mg, 0.278 mmole) obtained in the precedingstep (a) was subjected to deprotection and post-treatment with anisole(0.3 ml) and trifluoroacetic acid (3.0 ml) according to Example 73 togive the trifluoroacetatic acid salt of the title compound,4(5H),10-dioxo-7-(3-(1-piperidinyl)propoxy)-1H-1,2,3-triazolo 4,5-c!1!benzazepine (81 mg, 62%).

¹ H-NMR (D₂ O): δ1.40-1.55 (1H, m), 1.63-1.85 (3H, m), 1.85-2.00 (2H,m), 2.06-2.18 (2H, m), 2.94 (2H, dt), 3.24 (2H, t), 3.59 (2H, d),3.65-3.80 (2H, m), 6.00 (1H, s), 6.10 (1H, d), 7.52 (1H, d).

SIMS: m/z 356 (M⁺ +1-CF₃ CO₂ H).

Example 83

7-(3-(N,N-dimethylamino)propoxy)-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine

(a) To the solution of7-(3-chloropropoxy)-1-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine (116 mg, 0.272 mmole) obtained in Example 81 (a) inN,N-dimethylformamide (3 ml) were added potassium carbonate (752 mg,5.44 mmole), dimethylamine hydrochloride (444 mg, 5.45 mmole) and sodiumiodide (204 mg, 1.36 mmole). The reaction mixture was subjected toreaction and post-treatment in the same manner as in Example 81 (b) togive1-(4-methoxybenzyl)-7-(3-(N,N-dimethylamino)-propoxy)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine (113 mg, 95%).

¹ H-NMR (DMSO-d₆): δ1.88 (2H, quintet), 2.14 (6H, s), 2.35 (2H, t), 3.71(3H, s), 4.09 (2H, t), 6.01 (2H, s), 6.85-6.95 (1H, m), 6.89 (2H, d),7.06 (1H, d), 7.27 (2H, d), 8.14 (1H, d), 11.18 (1H, s).

EIMS: m/z 436 (M⁺ +1).

(b)1-(4-methoxybenzyl)-7-(3-(N,N-dimethylamino)propoxy)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine (167 mg, 0.383 mmole) obtained in the precedingstep (a) was subjected to deprotection and post-treatment with anisole(0.4 ml) and trifluoroacetic acid (4.0 ml) according to Example 73 togive the trifluoroacetatic acid salt of the title compound,7-(3-(N,N-dimethylamino)propoxy)-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine (128 mg, 78%).

¹ H-NMR (D₂ O): δ2.05-2.25 (2H, m), 2.95 (6H, s), 3.34 (2H, t), 3.78(2H, s), 6.04 (1H, s), 6.16 (1H, d), 7.55 (1H, d).

SIMS: m/z 316 (M⁺ +1-CF₃ CO₂ H).

Example 84

8-(4-methoxyphenacyloxy)-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine

(a) 8-hydroxy-1-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine (95.2 mg, 0.27 mmole) obtained in Example 39 (f)was dissolved in N,N-dimethylformamide (3 ml). Potassium carbonate (56.6mg, 0.41 mmole) and 4-methoxyphenacyl bromide (93.9 mg, 0.41 mmole) wereadded, and the mixture was stirred at room temperature for 140 minutes.The reaction mixture was subjected to post-treatment in the same manneras is Example 73 to give1-(4-methoxybenzyl)-8-(4-methoxyphenacyloxy)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine as a yellow crystalline powder (134.5 mg, 99%).

¹ H-NMR (DMSO-d₆): δ3.71 (3H, s), 3.87 (3H, s), 5.61 (2H, s), 5.97 (2H,s), 6.88 (2H, d), 7.10 (2H, d), 7.25 (1H, d), 7.44 (1H, dd), 7.50 (1H,d), 7.58 (1H, d), 8.01 (2H, d), 11.29 (1H, brs).

EIMS: m/z 498 (M⁺).

(b) To1-(4-methoxybenzyl)-8-(4-methoxyphenacyloxy)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine (134.5 mg, 0.27 mmole) obtained in the precedingstep (a) were added anisole (0.3 ml) and trifluoroacetic acid (3 ml),and the mixture was stirred at 60° C. for 30 minutes, and then subjectedto post-treatment in the same way as in Example 73 to give the titlecompound, 8-(4-methoxyphenacyloxy)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine as a yellow powder (98.1 mg, 96%).

¹ H-NMR (DMSO-d₆): δ3.87 (3H, s), 5.62 (2H, s), 7.10 (2H, d), 7.44 (1H,dd), 7.54(1H, d), 7.69 (1H, d), 8.02 (2H, d), 11.37 (1H, brs).

SIMS: m/z 379 (M⁺ +1).

Example 85

8-(2-methoxyethoxy)-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine

(a) 8-hydroxy-1-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine (300 mg, 0.86 mmole) obtained in Example 39 (f) wasdissolved in N,N-dimethylformamide (9 ml). Potassium carbonate (178 mg,1.29 mmole), 2-methoxyethyl chloride (117 μl, 1.29 mmole) and sodiumiodide (193 mg, 1.29 mmole) were added, and the mixture was stirred at atemperature in the range of 100° C.-120° C. for 3 hours. The reactionmixture was subjected to post-treatment in the same manner as is Example73 to give1-(4-methoxybenzyl)-8-(2-methoxyethoxy)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine as a yellowish green crystalline powder (181.9 mg,51%).

¹ H-NMR (DMSO-d₆): δ3.35 (3H, s), 3.67 (2H, t), 3.71 (3H, s), 4.16 (2H,t), 6.00 (2H, s), 6.90 (2H, d), 7.29 (2H, d), 7.40 (1H, dd), 7.49 (1H,d), 7.59 (1H, d), 11.30 (1H, brs).

EIMS: m/z 408 (M⁺).

(b)1-(4-methoxybenzyl)-8-(2-methoxyethoxy)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine (181.9 mg, 0.45 mmole) obtained in the precedingstep (a) was subjected to de-protection and post-treatment with anisole(0.5 ml) and trifluoroacetic acid (5 ml) in the same manner as inExample 73 to give the title compound,8-methoxyethoxy-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c! 1!benzazepine asa green powder (120.2 mg, 94%).

¹ H-NMR (DMSO-d₆): δ3.31 (3H,s), 3.68 (2H, t), 4.17 (2H, t), 7.40 (1H,dd), 7.53 (1H, d), 7.72 (1H, d), 11.36 (1H, brs).

EIMS: m/z 288 (M⁺).

Example 86

4(5H),10-dioxo-8-(3-phenoxypropyloxy)-1H-1,2,3-triazolo 4,5-c!1!benzazepine

(a) 8-hydroxy-1-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine (150.0 mg, 0.43 mmole) obtained in Example 39 (f)was dissolved in the mixture of acetone (4 ml) and N,N-dimethylformamide(2 ml). Potassium carbonate (89.0 mg, 0.65 mmole) and 3-phenoxypropylbromide (103 μl, 0.65 mmole) were added, and the mixture was stirred at60° C. for 140 minutes. The reaction mixture was subjected topost-treatment in the same manner as is Example 73 to give1-(4-methoxybenzyl)-4(5H),10-dioxo-8-(3-phenoxypropyloxy)-1H-1,2,3-triazolo4,5-c! 1!benzazepine as a yellow crystalline powder (134.8 mg, 65%).

¹ H-NMR (DMSO-d₆): δ2.10-2.25 (2H, m), 3.71 (3H, s), 4.13 (2H, t), 4.20(2H, t), 5.99 (2H, s), 6.81-7.10 (5H, m), 7.22-7.35 (4H, m), 7.41 (1H,dd), 7.49 (1H, d), 7.61 (1H, d), 11.30 (1H, brs).

EIMS: m/z 484 (M⁺).

(b)1-(4-methoxybenzyl)-4(5H),10-dioxo-8-(3-phenoxypropyloxy)-1H-1,2,3-triazolo4,5-c! 1!benzazepine (134.8 mg, 0.28 mmole) obtained in the precedingstep (a) was subjected to de-protection and post-treatment with anisole(0.3 ml) and trifluoroacetic acid (3 ml) in the same manner as inExample 73 to give the title compound,4(5H),10-dioxo-8-(3-phenoxypropyloxy)-1H-1,2,3-triazolo 4,5-c!1!benzazepine as a yellow powder (90.6 mg, 89%).

¹ H-NMR (DMSO-d₆): δ2.10-2.27 (2H, m), 4.14 (2H, t), 4.22 (2H, t),6.90-7.00 (3H, m), 7.25-7.30 (2H, d), 7.41 (1H, dd), 7.53 (1H, d), 7.74(1H, d), 11.39 (1H, brs).

EIMS: m/z 365 (M⁺ +1).

Example 87

8-(2-methoxyphenacyloxy)-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine

(a) 8-hydroxy-1-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine (100.0 mg, 0.29 mmole) obtained in Example 39 (f)was dissolved in N,N-dimethylformamide (3 ml). Potassium carbonate (61mg, 0.44 mmole) and 2-methoxyphenacyl bromide (101 mg, 0.44 mmole) wereadded, and the mixture was stirred at room temperature for 3 hours. Thereaction mixture was subjected to post-treatment in the same manner asis Example 73 to give1-(4-methoxybenzyl)-8-(2-methoxyphenacyloxy)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine as a yellow crystalline powder (134.6 mg, 95%).

¹ H-NMR (DMSO-d₆): δ3.70 (3H, s), 3.98 (3H, s), 5.41 (2H, s), 5.97 (2H,s), 6.87 (2H, d), 7.10 (1H, t), 7.22-7.35 (3H, m), 7.40 (1H, dd), 7.50(1H, d), 7.51 (1H, d), 7.64 (1H, ddd), 7.71 (1H, dd), 11.30 (1H, brs).

SIMS: m/z 499 (M⁺ +1).

(b)1-(4-methoxybenzyl)-8-(2-methoxyphenacyloxy)-4,5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine (60.7 mg, 0.12 mmole) obtained in the precedingstep (a) was subjected to deprotection and post-treatment with anisole(0.2 ml) and trifluoroacetic acid (2 ml) in the same manner as inExample 73 to give the title compound,8-(2-methoxyphenacyloxy)-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine as a yellow powder (43.2 mg, 94%).

¹ H-NMR (DMSO-d₆): δ3.99 (3H, s), 5.41 (2H, s), 7.10 (1H, t), 7.27 (1H,d), 7.41 (1H, dd), 7.54 (1H, d), 7.60-7.68 (2H, m), 7.72 (1H, dd), 11.37(1H, brs).

FDMS: m/z 378 (M⁺).

Example 88

8-(3-(N,N-dimethylamino)propyloxy)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c!1!benzazepine

(a) 8-hydroxy-1-(4-methoxybenzyl)-4(5H), 10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine (200 mg, 0.57 mmole) obtained in Example 39 (f) wasdissolved in N,N-dimethylform-amide (6 ml). Potassium carbonate (158 mg,1.14 mmole) and 3-chloro-1-iodopropane (122 μl, 1.14 mmole) were added,and the mixture was stirred at room temperature for 17.5 hours. Thereaction mixture was subjected to post-treatment in the same manner asis Example 73 to give 8-(3-chloropropyloxy)-1-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c! 1!benzazepine as a yellow crystallinepowder (181.5 mg, 76%).

¹ H-NMR (DMSO-d₆): δ2.19 (2H, t), 3.71 (3H, s), 3.81 (2H, t), 4.15 (2H,t), 6.00 (2H, s), 6.90 (2H, d), 7.29 (2H, d), 7.40 (1H, dd), 7.50 (1H,d), 7.60 (1H, d), 11.37 (1H, brs).

SIMS: m/z 428 (M⁺ +1).

(b)8-(3-chloropropyloxy)-1-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine (130 mg, 0.3 mmole) obtained in the preceding step(a) was dissolved in N,N-dimethylformamide (3 ml). Potassium carbonate(829 mg, 6.0 mmole) and N,N-dimethylamine hydrochloride (489 mg, 6.0mmole) were added, and the mixture was stirred at 60° C. for 20 hours.After the reaction mixture was diluted with water (20 ml), the resultingprecipitates were collected by filtration and pulverized with diethylether to give1-(4-methoxybenzyl)-8-(3-(N,N-dimethylamino)propyloxy)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine as a yellow powder (99.1 mg, 75%).

¹ H-NMR (DMSO-d₆): δ1.82-1.89 (2H, m), 2.14 (6H, s), 2.35 (2H, t), 3.71(3H, s), 4.04 (2H, t), 6.00 (2H, s), 6.90 (2H, d), 7.28 (2H, d), 7.33(1H, dd), 7.44 (1H, d), 7.56 (1H, d), 11.26 (1H, brs).

EIMS: m/z 435 (M⁺ +1).

(c)1-(4-methoxybenzyl)-8-(3-(N,N-dimethylamino)propyloxy)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine (93.1 mg, 0.21 mmole) obtained in the precedingstep (b) was subjected to deprotection and post-treatment with anisole(0.3 ml) and trifluoroacetic acid (3 ml) in the same manner as inExample 63 to give the trifluoroacetic acid salt of the title compound,8-(3-(N,N-dimethylamino)propyloxy)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine as a yellow powder (87.8 mg, 96%).

¹ H-NMR (DMSO-d₆): δ2.09-2.20 (2H, m), 2.83 (6H, s), 3.26 (2H, t), 4.14(2H, t), 7.39 (1H, dd), 7.55 (1H, d), 7.75 (1H, d), 9.54 (1H, brs),11.40 (1H, brs).

SIMS: m/z 316 (M⁺ +1).

Example 89

8-(2-oxo-4-phenylbutoxy)-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine

(a) 8-hydroxy-1-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine (200 mg, 0.57 mmole) obtained in Example 39 (f) wasdissolved in N,N-dimethylformamide (6 ml). Potassium carbonate (119 mg,0.86 mmole) and 2-oxo-4-phenylbutoxy bromide (119 mg, 0.86 mmole) wereadded, and the mixture was stirred at room temperature for 7 hours. Thereaction mixture was subjected to post-treatment in the same manner asis Example 73 to give1-(4-methoxybenzyl)-4(5H),10-dioxo-8-(2-oxo-4-phenylbutoxy)-1H-1,2,3-triazolo4,5-c! 1!benzazepine as a yellow crystalline powder (278.6 mg, 95%).

¹ H-NMR (DMSO-d₆): δ2.80-2.92 (4H, m), 3.71 (3H, s), 4.93 (2H, s), 5.99(2H, s), 6.90 (2H, d), 7.10-7.30 (7H, m), 7.34 (1H, dd), 7.48 (1H, d),7.53 (1H, d), 11.31 (1H, s).

SIMS: m/z 497 (M⁺ +1).

(b)1-(4-methoxybenzyl)-4(5H),10-dioxo-8-(2-oxo-4-phenylbutoxy)-1H-1,2,3-triazolo4,5-c! 1!benzazepine (269.9 mg, 0.54 mmole) obtained in the precedingstep (a) was subjected to deprotection and post-treatment with anisole(0.6 ml) and trifluoroacetic acid (6 ml) in the same manner as inExample 73 to give the title compound,4(5H),10-dioxo-8-(2-oxo-4-phenylbutoxy)-1H-1,2,3-triazolo 4,5-c!1!benzazepine as a yellow powder (177.5 mg, 87%).

¹ H-NMR (DMSO-d₆): δ2.77-2.95 (4H, m), 4.95 (2H, s), 7.15-7.33 (5H, m),7.35 (1H, dd), 7.52 (1H, d), 7.66 (1H, d), 11.36 (1H, brs).

SIMS: m/z 377 (M⁺ +1).

Example 90

7-formyl-5-hydroxy-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c! 1!benzazepine

(a) In the preparation of 5-(2-amino-4-dimethoxymethylbenzoyl)1-(4-methoxybenzyl)-1,2,3-triazole-4-carboxylate (c-2: MP) in Example 11(c-2), 5-(2-hydroxyamino-4-dimethoxymethylbenzoyl)1-(4-methoxybenzyl)-1,2,3-triazole-4-carboxylate can be also obtained asa by-product. To a solution of5-(2-hydroxyamino-4-dimethoxymethylbenzoyl)1-(4-methoxybenzyl)-1,2,3-triazole-4-carboxylate (883 mg, 1.94 mmole) inmethanol (10 ml) was added a 28% methanolic sodium methoxide solution(0.95 ml), and the mixture was stirred at room temperature for 22 hours.The reaction mixture was diluted with a 1N aqueous hydrochloric acidsolution (3 ml) and diethyl ether. The resulting precipitates werecollected by filtration, pulverized with diethyl ether, and desiccatedto give5-hydroxy-1-(4-methoxybenzyl)-7-dimethoxymethyl-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine (432 mg, 52.5%).

¹ H-NMR (DMSO-d₆): δ3.28 (3H, s), 3.71 (3H, s), 5.53 (1H, s), 5.89 (2H,s), 6.91 (2H, d), 7.31 (2H, d), 7.41 (1H, d), 8.03 (1H, s), 8.04 (1H,d), 11.43 (1H, brs).

FDMS: m/z 424 (M⁺).

(b) To a solution of5-hydroxy-1-(4-methoxybenzyl)-7-dimethoxymethyl-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine (94 mg, 0.221 mmole) in tetrahydrofuran (4 ml)was-added a 1N aqueous hydrochloric acid solution (1 ml), and themixture was stirred at room temperature for 13.5 hours. The reactionmixture was extracted with ethyl acetate, and the organic layer waswashed with a saturated aqueous saline. After the organic layer wasdried over anhydrous magnesium sulfate, the solvent was removed underreduced pressure to give7-formyl-5-hydroxy-1-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine as a yellow powder (76 mg, 90.9%).

¹ H-NMR (DMSO-d₆): δ3.72 (3H, s), 5.89 (2H, s), 6.91 (2H, d), 7.32 (2H,d), 7.85 (1H, d), 8.20 (1H, d), 8.47 (1H, s), 10.15 (1H, brs), 11.63(1H, s).

FDMS: m/z 379 (M⁺ +1).

(c) To7-formyl-5-hydroxy-1-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine (76 mg, 0.201 mmole) obtained in the preceding step(b) was added trifluoroacetic acid (1 ml), and the mixture was stirredat 70° C. for 30 minutes. The reaction mixture was then concentratedunder reduced pressure, and the resulting precipitates were collected byfiltration, washed with ethyl acetate, and desiccated to give the titlecompound, 7-formyl-5-hydroxy-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine as a yellow crystalline powder (20 mg, 38.6%).

¹ H-NMR (DMSO-d₆): δ7.89 (1H, d), 8.36 (1H, d), 8.54 (1H, s), 10.18 (1H,brs), 11.69 (1H, brs).

FDMS: m/z 258 (M⁺ +1).

Example 91

4(5H),10-dioxo-7-(p-toluoylamino)-1H-1,2,3-triazolo 4,5-c! 1!benzazepine

(a) To a solution of diisopropylamine (0.11 ml, 0.82 mmole) intetrahydrofuran (2 ml) at -78° C. was added under the argon atmosphere1.5N butyllithium (0.51 ml, 0.77 mmole), and the mixture was stirred for30 minutes. Next, to this reaction mixture were added ethyl propiolate(93 μl, 0.92 mmole) followed by a solution of2-nitro-4-(p-toluoylamino)-benzaldehyde (144.5 mg, 0.51 mmole), and themixture was further stirred at -78° C. for 1 hour. After a solution ofacetic acid (90 μl, 1.58 mmole) in tetrahydrofuran (1 ml) was added tothe reaction mixture, it was extracted with ethyl acetate. The organiclayer was washed with dilute hydrochloric acid, water, a saturatedaqueous sodium hydrogen carbonate solution, and a saturated aqueoussaline in this sequence. After the organic layer was dried overanhydrous magnesium sulfate, the solvent was removed under reducedpressure to give ethyl4-hydroxy-4-(2-nitro-4-(p-toluoylamino)-phenyl)-2-butynoate as an oil(176 mg). The product thus obtained was dissolved in toluene (2 ml),4-methoxybenzylazide (250 mg, 1.53 mmole), and the mixture was stirredwith heating at 100° C. for 5 hours. The reaction mixture was cooled toroom temperature, the resulting crystalline products were filtered togive the 1:1 mixture of ethyl4-(hydroxy-(2-nitro-4-(p-toluoylamino)phenyl)methyl)-1-(4-methoxybenzyl)-1,2,3-triazole-5-carboxylate(a-1) and ethyl5-(hydroxy-(2-nitro-4-(p-toluoylamino)phenyl)methyl)-1-(4-methoxybenzyl)-1,2,3-triazole-4-carboxylate(a-2) (103.4 mg, 37%).

The 1:1 mixture of a-1 and a-2;

¹ H-NMR (DMSO-d₆): δ1.26 (3/2H, t), 1.31 (3/2H, t), 2.40 (3H, s), 3.63(3/2H, s), 3.72 (3/2H, s), 4.28 (1H, q), 4.37 (1H, q), 5.44 (1/2H, d),5.56 (1/2H, d), 5.78 (1H, d), 6.30 (1/2H, d), 6.70 (1H, d), 6.72 (1H,d), 6.91 (2H, d), 7.00 (1/2H, d), 7.16 (2H, d), 7.37 (2H, d), 7.85(1/2H, dd), 7.89 (2H, d), 7.91 (1/2H, d), 8.05 (1/2H, d), 8.16 (1/2H,d), 8.37 (1/2H, d), 8.54 (1/2H, d), 10.53 (1/2H, s), 10.60 (1/2H, s).

SIMS: m/z 546 (M⁺ +1).

(b) To a solution of the 1:1 mixture (103.4 mg, 0.19 mmole) of ethyl4-(hydroxy-(2-nitro-4-(p-toluoylamino)phenyl)methyl)-1-(4-methoxybenzyl)-1,2,3-triazole-5-carboxylate(a-1) and ethyl5-(hydroxy-(2-nitro-4-(p-toluoylamino)phenyl)methyl)-1-(4-methoxybenzyl)-1,2,3-triazole-4-carboxylate(a-2) obtained in the preceding step (a) in chloroform (4 ml) was addedmanganese dioxide (300 mg), and the mixture was stirred at roomtemperature overnight. After the reaction mixture was filtered throughcelite, and washed with ethyl acetate, the solvent was removed underreduced pressure to give the 1:1 mixture of ethyl1-(4-methoxybenzyl)-4-(2-nitro-4-(p-toluoylamino)benzoyl)-1,2,3-triazole-5-carboxylate(b-1) and ethyl1-(4-methoxybenzyl)-5-toluoylaminoro-4-(p-toluoylamino)benzoyl)-1,2,3-triazole-4-carboxylate(b-2) as a yellowish brown oil (103 mg, 100%).

The 1:1 mixture of b-1 and b-2;

¹ H-NMR (DMSO-d₆): δ0.95 (3/2H, t), 1.23 (3/2H, t), 2.40 (3H, s), 3.68(3/2H, s), 3.74 (3/2H, s), 3.99 (1H, q), 4.33 (1H, q), 5.68 (1H, s),5.73 (1H, s), 6.86 (1H, d), 6.94 (1H, d), 7.23 (2H, d), 7.39 (2H, d),7.54 (1/2H, d), 7.78 (1/2H, d), 7.92 (1H, d), 7.94 (1H, d), 8.05 (1/2H,dd), 8.26 (1/2H, dd), 8.51 (1/2H, d), 8.71 (1/2H, d), 10.86 (1/2H, s),10.89 (1/2H, s).

SIMS: m/z 544 (M⁺ +1).

(c) The 1:1 mixture (103.4 mg, 0.19 mmole) of ethyl1-(4-methoxybenzyl)-4-(2-nitro-4-(p-toluoylamino)benzoyl)-1,2,3-triazole-5-carboxylate(b-1) and ethyl1-(4-methoxybenzyl)-5-(2-nitro-4-(p-toluoylamino)benzoyl)-1,2,3-triazole-4-carboxylate(b-2) obtained in the preceding step (b) was dissolved in ethyl acetate(2 ml), 10% palladium on carbon (12 mg) was added, and the mixture wasstirred under the hydrogen atmosphere at room temperature overnight. Thereaction mixture was filtered through celite, and the precipitates werecollected by filtration to give the 1:1 mixture (97.3 mg, 100%) of ethyl4-(2-nitro-4-(p-toluoylamino)benzoyl)-1-(4-methoxybenzyl)-1,2,3-triazole-5-carboxylate(c-1) and ethyl1-(4-methoxybenzyl)-5-(2-nitro-4-(p-toluoylamino)benzoyl)-1-(4-methoxybenzyl)-1,2,3-triazole-4-carboxylate(c-2).

The 1:1 mixture of c-1 and c-2;

¹ H-NMR (DMSO-d₆): δ1.00 (3H, t), 2.39 (3H, s), 3.66 (3/2H, s), 3.74(3/2H, s), 4.10 (1H, q), 4.16 (1H, q), 5.46 (1H, s), 5.83 (1H, s), 6.87(2H, d), 7.10 (2H, d), 7.15 (1H, dd), 7.22 (1H, d), 7.29 (2H, d), 7.85(1H, d), 7.87-7.93 (2H, m), 10.25 (1H, s).

SIMS: m/z 514 (M⁺ +1).

(d) Under the argon atmosphere, to a solution of the 1:1 mixture (91.5mg, 0.18 mmole) of ethyl4-(2-nitro-4-(p-toluoylamino)benzoyl)-1-(4-methoxybenzyl)-1,2,3-triazole-5-carboxylate(c-1) and ethyl1-(4-methoxybenzyl)-5-(2-nitro-4-(p-toluoylamino)benzoyl)-1-(4-methoxybenzyl)-1,2,3-triazole-4-carboxylate(c-2) obtained in the preceding step (c) in methanol (1 ml) underice-cooling was added 5.1M sodium methoxide (39 μl, 0.20 mmole). Themixture was stirred under ice-cooling for 20 minutes, and then at roomtemperature overnight. The reaction mixture was diluted with water, andthe resulting precipitates were collected by filtration, washed withdiethyl ether and water, and desiccated to give the 1:1 mixture of3-(4-methoxybenzyl)-4(5H),10-dioxo-7-(p-toluoylamino)-3H-1,2,3-triazolo5,4-c! 1!benzazepine (d-1) and1-(4-methoxybenzyl)-4(5H),10-dioxo-7-(p-toluoylamino)-1H-1,2,3-triazolo4,5-c! 1!benzazepine (d-2) as a yellow crystalline powder (53.1 mg,64%).

The 1:1 mixture of d-1 and d-2;

¹ H-NMR (DMSO-d₆): δ2.39 (3H, s), 3.70 (3H, s), 5.98 (1H, s), 6.13 (1H,s), 6.80-7.00 (3H, m), 7.20-7.40 (4H, m), 7.80 (1H, d), 7.89 (2H, d),8.11 (1H, d), 10.38 (1H, brs).

SIMS: m/z 468 (M⁺ +1).

(e) To the 1:1 mixture (48 mg, 0.10 mmole) of3-(4-methoxybenzyl)-4(5H),10-dioxo-7-(p-toluoylamino)-3H-1,2,3-triazolo5,4-c! 1!benzazepine (d-1) and1-(4-methoxybenzyl)-4(5H),10-dioxo-7-(p-toluoylamino)-1H-1,2,3-triazolo4,5-c! 1!benzazepine (d-2) obtained in the preceding step (d) were addedanisole (0.1 ml) and trifluoroacetic acid (1.0 ml), and the mixture wasstirred at 60° C. for 40 minutes. The solvent was then removed underreduced pressure. The resulting precipitates were collected byfiltration, washed with diethyl ether, and desiccated to give the titlecompound, 4(5H),10-dioxo-7-(p-toluoylamino)-1H-1,2,3-triazolo 4,5-c!1!benzazepine as a brown crystalline powder (35.7 mg, 100%).

¹ H-NMR (DMSO-d₆): δ2.40 (3H, s), 7.36 (2H, d), 7.62 (1H, d), 7.91 (2H,d), 8.16 (1H, s), 8.29 (1H, d), 10.65 (1H, s), 11.47 (1H, brs).

SIMS: m/z 347 (M⁺).

Example 92

10(9H)-oxo-1H-1,2,3-triazolo 4,5-b! 1,5!benzothiazepine

(a) Under the argon atmosphere, to an ice-cooled solution of2-aminobenzenethiol (0.20 ml, 1.87 mmole) in tetrahydrofuran (15 ml) wasadded 60% sodium hydride (76 mg, 1.90 mmole), and the mixture wasstirred at room temperature for 30 minutes. Ethyl5-chloro-1-(4-methoxybenzyl)-1,2,3-triazole-4-carboxylate (499 mg, 1.69mmole) was then added, and the mixture was stirred under ice-cooling for30 minutes and at room temperature for further 3 hours. The reactionmixture was diluted with water, extracted with ethyl acetate, and washedwith water and a saturated aqueous saline. The organic layer was driedover anhydrous magnesium sulfate, and the solvent was removed underreduced pressure. The residue was purified by chromatography on a silicagel column (hexane:ethyl acetate=3:1-1:4) to give ethyl5-(2-aminophenylthio)-1-(4-methoxybenzyl)-1,2,3-triazole-4-carboxylate(594 mg, 91.4%).

¹ H-NMR (DMSO-d₆): δ1.27 (3H, t), 3.71 (3H, s), 4.29 (2H, q), 5.55 (2H,s), 5.57 (2H, s), 6.48 (1H, dd), 6.72 (1H, d), 6.84 (2H, d), 7.03 (2H,d), 7.08 (1H, dd), 7.19 (1H, d).

EIMS: m/z 384 (M⁺).

(b) Under the argon atmosphere, to a solution of ethyl5-(2-aminophenylthio)-1-(4-methoxybenzyl)-1,2,3-triazole-4-carboxylate(52 mg, 0.135 mmole) in dimethylsulfoxide (15 ml) was added underice-cooling 60% sodium hydride (12.6 mg, 0.315 mmole), and the mixturewas stirred at room temperature for 2 hours. The reaction mixture wasdiluted with water, extracted with ethyl acetate, and washed with waterfollowed by a saturated aqueous saline. The organic layer was dried overanhydrous magnesium sulfate, and the solvent was removed under reducedpressure. The residue was purified by chromatography on a silica gelcolumn (hexane:ethyl acetate=1:4) to give3-(4-methoxybenzyl)-10(9H)-oxo-3H-1,2,3-triazolo 5,4-c!1,5!benzothiazepine as a colorless crystalline powder (40 mg, 87.6%).

¹ H-NMR (DMSO-d₆): δ3.80 (3H, s), 5.56 (2H, s), 6.88 (2H, d), 7.14-7.19(1H, m), 7.22-7.29 (3H, m), 7.36-7.40 (2H, m), 8.42 (1H, brs).

EIMS: m/z 338 (M⁺).

(c) To 3-(4-methoxybenzyl)-10(9H)-oxo-3H-1,2,3-triazolo 5,4-c!1,5!benzothiazepine (301 mg, 0.89 mmole) were added anisole (3.0 ml) andtrifluoroacetic acid (12 ml), and the mixture was stirred at 65° C. for1.5 hours. The reaction mixture was concentrated under reduced pressure,and the residue was dissolved in ethyl acetate, washed with waterfollowed by a saturated aqueous saline. The organic layer was dried overanhydrous magnesium sulfate, and the solvent was removed under reducedpressure. The resulting crystalline powder was collected by filtration,and washed with diethyl ether to give the title compound as a colorlesscrystalline powder (162 mg, 83.6%).

¹ H-NMR (DMSO-d₆): δ7.20 (1H, ddd), 7.30 (1H, dd), 7.42 (1H, ddd), 7.55(1H, dd), 10.66 (1H, brs).

EIMS: m/z 218 (M⁺).

Example 93

10(9H)-oxo-1H-1,2,3-triazolo 4,5-b! 1,5!benzothiazepine 4-oxide

(a) To a solution of 3-(4-methoxybenzyl)-10(9H)-oxo-3H-1,2,3-triazolo5,4-c! 1,5!benzothiazepine (401 mg, 1.19 mmole) in methylene chloride(32 ml) was added under the argon atmosphere a solution of 70%m-chloroperbenzoic acid (320 mg, 1.30 mmole) in methylene chloride (8.0ml), and the mixture was stirred at room temperature for 18 hours. Thereaction mixture was diluted with a saturated aqueous sodium hydrogencarbonate solution, extracted with ethyl acetate, and washed with asaturated aqueous sodium hydrogen carbonate, followed by a saturatedaqueous saline. The organic layer was dried over anhydrous magnesiumsulfate, and the solvent was removed under reduced pressure. The residuewas pulverized with diethyl ether to give3-(4-methoxybenzyl)-10(9H)-oxo-3H-1,2,3-triazolo 5,4-b!1,5!benzothiazepine 4-oxide as a colorless crystalline powder (388 mg,92.0%).

¹ H-NMR (DMSO-d₆): δ3.73 (3H, s), 5.90 (2H, s), 6.93 (2H, d), 7.31 (2H,d), 7.37 (1H, d), 7.44 (1H, d), 7.62 (1H, dd), 7.70 (1H, d), 11.20 (1H,s).

(b) To 3-(4-methoxybenzyl)-10(9H)-oxo-3H-1,2,3-triazolo 5,4-b!1,5!benzothiazepine 4-oxide (388 mg, 1.09 mmole) were added anisole (5.0ml) and trifluoroacetic acid (15 ml), and the mixture was stirred at 65°C. for 1.5 hours. The reaction mixture was concentrated under reducedpressure, and the residue was dissolved in an aqueous sodium hydroxidesolution, and washed with diethyl ether. The aqueous layer was acidifiedwith hydrochloric acid, extracted with ethyl acetate, and washed withwater and a saturated aqueous saline in this sequence. The organic layerwas dried over anhydrous magnesium sulfate, and the solvent was removedunder reduced pressure. The resulting powder was collected by filtrationto give the title compound as a colorless crystalline powder (194 mg,76.0%).

¹ H-NMR (DMSO-d₆): δ7.41 (1H, dd), 7.47 (1H, d), 7.65 (1H, dd), 7.92(1H, d), 11.28 (1H, s).

FDMS: m/z 234 (M⁺).

Example 94

10(9H)-oxo-1H-1,2,3-triazolo 4,5-b! 1,5!benzothiazepine 4,4-dioxide

(a) To a solution of 3-(4-methoxybenzyl)-10(9H)-oxo-3H-1,2,3-triazolo5,4-b! 1,5!benzo-thiazepine (29 mg, 0.0857 mmole) in ethylene chloride(10 ml) were added under the argon atmosphere 70% m-chloroperbenzoicacid (41 mg, 0.163 mmole) and 4,4'-thiobis(6-tert-butyl-m-cresol) (0.7mg, 0.00195 mmole). After stirring at 60° C. for 22.5 hours, 70%m-chloroperbenzoic acid (24 mg, 0.0974 mmole) was added, and the mixturewas stirred at 60° C. for 4 hours. The reaction mixture was diluted witha saturated aqueous sodium hydrogen carbonate solution, extracted withethyl acetate, and washed with a saturated aqueous sodium hydrogencarbonate and a saturated aqueous saline in this sequence. After theorganic layer was dried over anhydrous magnesium sulfate, the solventwas removed under reduced pressure to give3-(4-methoxybenzyl)-10(9H)-oxo-3H-1,2,3-triazolo 5,4-b!1,5!benzothiazepine 4,4-dioxide as a crude product (35 mg).

¹ H-NMR (DMSO-d₆): δ3.73 (3H, s), 5.89 (2H, s), 6.94 (2H, d), 7.32 (2H,d), 7.50 (1H, dd), 7.55 (1H, dd), 7.82 (1H, dd), 11.64 (1H, brs).

EIMS: m/z 370 (M⁺).

(b) To the crude product obtained in the preceding step (a) were addedanisole (0.50 ml) and trifluoroacetic acid (2.0 ml), and the mixture wasstirred at 65° C. for 1.5 hours. The reaction mixture was thenconcentrated under reduced pressure. The residue was dissolved in anaqueous sodium hydroxide solution, and purified on a DIAION HP-20 column(water: acetone=8:2) to give the sodium salt of10(9H)-oxo-1H-1,2,3-triazolo 4,5-b! 1,5!benzothiazepine 4,4-dioxide as acolorless powder (12.2 mg, 52.3%).

¹ H-NMR (DMSO-d₆): δ7.32 (1H, dd), 7.41 (1H, dd), 7.61 (1H, dd), 7.93(1H, dd), 10.66 (1H, s).

FDMS: m/z 295 (M⁺ +Na).

                                      TABLE 1                                     __________________________________________________________________________     ##STR8##                                                                     EXAMPLE NO.                                                                           R.sup.1                                                                         R.sup.2                                                                         R.sup.3                                                                         R.sup.4                                                                           R.sup.5                                                                         R            POSITION                                     __________________________________________________________________________    1       H H H H   H H            1                                            2       H H H H   H                                                                                ##STR9##    3                                            3       H Me                                                                              H H   H H            1                                            4       H H Me                                                                              H   H H            1                                            5       H H H Me  H H            1                                            6       H H H H   Me                                                                              H            1                                            8       H H H OH  H H            1                                            9       Me                                                                              H H H   H H            1                                            10      Me                                                                              H H H   H                                                                                ##STR10##   3                                            __________________________________________________________________________

                  TABLE 2                                                         ______________________________________                                         ##STR11##                                                                    EXAMPLE NO.  R.sup.3        R.sup.4                                           ______________________________________                                        11           CHO            H                                                 12           CH.sub.2 CH.sub.3                                                                            H                                                 13           CHCH.sub.2     H                                                 14           CH.sub.2 CH.sub.2 CH.sub.3                                                                   H                                                 15           CH.sub.2 (CH.sub.2).sub.6 CH.sub.3                                                           H                                                 16           CHCHCO.sub.2 CH.sub.3 (E)                                                                    H                                                 17           CH.sub.2 CH.sub.2 CO.sub.2 CH.sub.3                                                          H                                                 18           CHCHCO.sub.2 H(E)                                                                            H                                                 19           CHCHCN(E) + (Z)                                                                              H                                                 20           CHCHCOCH.sub.3 (E)                                                                           H                                                 21           CH(CH.sub.3).sub.2                                                                           H                                                 22           COCH.sub.3     H                                                 23           CH.sub.2 OCH.sub.3                                                                           H                                                 24           CO.sub.2 CH.sub.3                                                                            H                                                 25           OH             H                                                 26           OCH.sub.3      H                                                 27           OCH.sub.2 CH.sub.3                                                                           H                                                 28           OCH.sub.2 CHCH.sub.2                                                                         H                                                 29           OCH(CH.sub.3).sub.2                                                                          H                                                 30           OCH.sub.2 C.sub.6 H.sub.11                                                                   H                                                 31           OCH.sub.2 C.sub.6 H.sub.5                                                                    H                                                 32           OCH.sub.2 CO.sub.2 CH.sub.3                                                                  H                                                 33           OCH.sub.2 CO.sub.2 H                                                                         H                                                 34           OCH.sub.3 COCH.sub.3                                                                         H                                                 35           OCH.sub.2 CN   H                                                 36           OCH.sub.2 CONH.sub.2                                                                         H                                                 37           OCH.sub.2 COC.sub.6 H.sub.4 OCH.sub.3 -p                                                     H                                                 38           OCH.sub.2 CH.sub.2 OCH.sub.3                                                                 H                                                 39           H              OH                                                40           H              OCH.sub.2 CH.sub.3                                41           H              OCH.sub.3                                         42           H              OCH.sub.2 CO.sub.2 CH.sub.3                       43           OCH.sub.3      OCH.sub.3                                         44           CH.sub.3       CH.sub.3                                          45           CH.sub.3       OCH.sub.3                                         46           CH.sub.3       H                                                 ______________________________________                                    

                  TABLE 3                                                         ______________________________________                                         ##STR12##                                                                    EXAMPLE NO.                                                                              R.sup.1                                                                              R.sup.3 R         POSITION                                  ______________________________________                                        47         H      CH.sub.3                                                                              CH.sub.2 C.sub.6 H.sub.4 OCH.sub.3 -P                                                   1                                         47         H      CH.sub.3                                                                              CH.sub.2 C.sub.6 H.sub.4 OCH.sub.3 -P                                                   3                                         48         H      CH.sub.3                                                                              CH.sub.2 C.sub.6 H.sub.4 OCH.sub.3 -P                                                   3                                         49         CH.sub.3                                                                             H       H         1                                         ______________________________________                                    

                                      TABLE 4                                     __________________________________________________________________________     ##STR13##                                                                    EXAMPLE NO.                                                                            R.sup.3            R.sup.4                                           __________________________________________________________________________    50       CHC(CH.sub.3)CO.sub.2 CH.sub.3 (E)                                                               H                                                 51       CHCHCOC.sub.6 H.sub.4 OCH.sub.3 -p(E)                                                            H                                                 52       CHCHCONHCH.sub.2 CH.sub.2 N(CH.sub.3).sub.2 (E)                                                  H                                                 53       CHCHCONHCH.sub.2 C.sub.6 H.sub.5 (E)                                                             H                                                 54                                                                                      ##STR14##         H                                                 55       CHCHCONHCH.sub.2   H                                                           ##STR15##                                                           56                                                                                      ##STR16##         H                                                 57       CHNOH              H                                                 58       CHNOCH.sub.3       H                                                 59       CHNOCH.sub.2 C.sub.6 H.sub.5                                                                     H                                                 60       CH.sub.2 NHCH.sub.2 CH.sub.2 CH.sub.3                                                            H                                                 61       CH.sub.2 N(CH.sub.2 CH.sub.2 CH.sub.3)COCH.sub.3                                                 H                                                 62       CH.sub.2 N(CH.sub.2 CH.sub.2 CH.sub.3)COCH.sub.2 CH.sub.2                     CO.sub.2 H         H                                                 63       CH.sub.2 NHCH.sub.2 C.sub.6 H.sub.5                                                              H                                                 64       CH.sub.2 N(CH.sub.2 C.sub.6 H.sub.5)COCH.sub.3                                                   H                                                 65       CH.sub.2 NHCH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                                   H                                                 66       CH.sub.2 NHCOCH.sub.2 CH.sub.2 CH.sub.2 CO.sub.2 H                                               H                                                 67       CH.sub.2 NHCOCH.sub.3                                                                            H                                                 68       CH.sub.2 NHSO.sub.2 CH.sub.2                                                                     H                                                 69       CH.sub.2 NHSO.sub.2 C.sub.6 H.sub.5                                                              H                                                 70       CH.sub.2 NHSO.sub.2 C.sub.6 H.sub.4 F-p                                                          H                                                 71       CH.sub.2 NHSO.sub.2 C.sub.6 H.sub.4 Cl-p                                                         H                                                 72       CH(C.sub.6 H.sub.4 OCH.sub.3 -p).sub.2                                                           H                                                 73       OCH.sub.2 COC.sub.6 H.sub.4 OCH.sub.3 -o                                                         H                                                 74       OCH.sub.2 COC.sub.6 H.sub.4 Cl-p                                                                 H                                                 75       OCH.sub.2 CH.sub.2 CH.sub.2 OC.sub.6 H.sub.5                                                     H                                                 76       OCH.sub.2 CH.sub.2 CH.sub.2 C.sub.6 H.sub.5                                                      H                                                 77       OCH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 C.sub.6 H.sub.5                                             H                                                 78       OCH.sub.2 CH.sub.2 OC.sub.6 H.sub.5                                                              H                                                 79       OCH.sub.2 COCH.sub.2 CH.sub.2 C.sub.6 H.sub.5                                                    H                                                 80       OCH.sub.2 CH(OH)CH.sub.2 CH.sub.2 C.sub.6 H.sub.5                                                H                                                 81                                                                                      ##STR17##         H                                                 82                                                                                      ##STR18##         H                                                 83       OCH.sub.2 CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                                    H                                                 84       H                  OCH.sub.2 COC.sub.6 H.sub.4 OCH.sub.3 -p          85       H                  OCH.sub.2 CH.sub.2 OCH.sub.3                      86       H                  OCH.sub.2 CH.sub.2 CH.sub.2 OC.sub.6 H.sub.5      87       H                  OCH.sub.2 COC.sub.6 H.sub.4 OCH.sub.3 -o          88       H                  OCH.sub.2 CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                 1                                                 89       H                  OCH.sub.2 COCH.sub.2 CH.sub.2 C.sub.6                                         H.sub.5                                           91       NHCOC.sub.6 H.sub.4 CH.sub.3 -p                                                                  H                                                 __________________________________________________________________________

                  TABLE 5                                                         ______________________________________                                         ##STR19##                                                                    EXAMPLE NO.  R.sup.1                                                                             R.sup.2 R.sup.3                                                                           R.sup.4                                                                              R.sup.5                                                                           n                                   ______________________________________                                        92           H     H       H   H      H   0                                   93           H     H       H   H      H   1                                   94           H     H       H   H      H   2                                   ______________________________________                                    

Preparationl Example 1

    ______________________________________                                        Tablet                                                                        Compound of Example 46  2.5   g                                               Lactose                 12    g                                               6% HPC lactose          8     g                                               Potato starch           2     g                                               Magnesium stearate      0.5   g                                               Total                   25    g                                               ______________________________________                                    

Preparation Example 2

    ______________________________________                                        Capsule                                                                       Compound of Example 46  2.5   g                                               Lactose                 18    g                                               Potato starch           4     g                                               Magnesium stearate      0.5   g                                               Total                   25    g                                               ______________________________________                                    

All of them are blended sufficiently and filled into hard capsules toprepare 1,000 capsules.

Pharmacological Test 1

Test of suppressing histamine releasing reaction

(1) Preparation of anti-serum

Rat anti-dinitrophenylated ascaris protein (referred to hereinafter asDNP-As) serum was prepared according to the method described by Tada, T.and Okumura, K., J. Immun., 106 (4), 1971. Briefly, 1×10¹⁰ of inviablepertussis and 1 mg of DNP-As were administered subcutaneously to the pawof female Brown Norway rats having a body weight of 200 g. After fivedays, 0.5 mg of DNP-As was further administered intramuscularly to therear of the animals. Blood samples were taken after three days of theadministration to prepare anti-serum. The anti-serum had a titer of1:1,000-1:2,000 measured by the passively immunized cutaneousanaphylaxis reaction for 48 hours in rats.

(2) Induction of histamine releasing reaction and suppression of thereleasing reaction by the drugs

A 1 ml portion of the serum diluted four times with physiological salinewas administered intraperitoneally to male Wister rats. After two days,abdominal cavity was rinsed with phosphate buffer to recover the cellswithin the abdominal cavity. After the cell concentration was adjustedto 10⁵ cell/ml, the cells were stimulated with 1 μg/ml of DNP-As. Theamount of histamine released into the supernatant was measured accordingto the method described by Shore, P. A., Burkhalter, A. H. and Chon, V.H. Jr., J. Pharm. Exp. Ther., 127, 182-186 (1959).

A dose for suppressing 50% of the histamine releasing reaction, i.e.,IC₅₀ value, was calculated from the amounts of histamine released in thegroup treated with the test compounds in the molar concentrations (M) of10⁻⁵ -10⁻¹⁰ and in the control group. The IC₅₀ value as the suppressingeffect of the drugs is shown in Table 6 with the IC₅₀ value of sodiumchromoglycic acid selected as the control compound.

As apparent from the result, the compound of the present inventionexhibited an excellent suppressing effect of the histamine releasingreaction.

                  TABLE 6                                                         ______________________________________                                        Compound No.   IC.sub.50 (nM)                                                 ______________________________________                                        1              12                                                             3              37                                                             4              2.3                                                            5              13                                                             12             6.2                                                            16             2.6                                                            17             4.1                                                            18             4.5                                                            19             4.3                                                            20             2.9                                                            27             8.6                                                            34             3.5                                                            37             7.5                                                            43             1.4                                                            44             8.5                                                            45             2.9                                                            46             2.3                                                            50             3.6                                                            51             7.8                                                            53             4.4                                                            54             3.6                                                            56             4.7                                                            57             2.4                                                            58             8.1                                                            68             3.5                                                            69             3.5                                                            70             6.1                                                            73             4.8                                                            74             4.5                                                            75             4.O                                                            78             3.6                                                            79             3.6                                                            80             4.7                                                            81             3.8                                                            84             3.9                                                            87             7.4                                                            DSCG*          1,800-700                                                      ______________________________________                                         * DSCG: sodium chromoglycate                                             

Pharmacological Test 2

Test for suppressing immediate and delayed allergic reaction

1×10¹⁰ of inviable pertussis and 1 mg of dinitrophenylated ovalbumin(DNP-OA) were administered subcutaneously to the three paws except theright hind paw of male Wister rats having a body weight of 200 g. After10 days, 5 μg of DNP-OA was further administered subcutaneously to theright hind paw of the animals to induce the allergic edema reaction atpaw. The allergy suppressing effect of the test compounds was examinedwith reference to the edema volumes after 30 minutes and 8 hours of theinduction of the allergic reaction as the immediate and delayed allergicreactions, respectively.

The suspension of the test compounds in 0.25% Tween 80 were administeredorally to rats at a dose of 10 mg/kg of body weight prior to theinduction of the allergic reaction. On the other hand, only a solutionof 0.25% Tween 80 was orally administered to rats as the untreatedcontrol, and 100 mg/kg of sodium chromoglycate subcutaneously or orallyto rats as the positive control.

The rate of suppressing the allergic edema reaction at paw wascalculated from the following equation. The rates of suppressing theimmediate and slow allergic edema reaction by the present compounds areshown in the following table. Suppression rate of the allergic edemareaction at paw

    (%)=(A-B)/A×100

wherein

A is an average edema volume in the control, and

B is an average edema volume in the drug treated group.

                  TABLE 7                                                         ______________________________________                                                    Suppressing Rate (%)                                              Test Compound No.                                                                           Immediate Reaction                                                                          Slow reaction                                     ______________________________________                                        1.sup.3)      56.4          24.5                                              3.sup.3)      46.6          24.2                                              4.sup.3)      70.5          57.7                                              5.sup.3)      48.7          28.9                                              12            59            53                                                16            79            80                                                20            63            51                                                27            48            55                                                43            59            53                                                46            64            68                                                69            50            41                                                84            48            40                                                DSCG.sup.1)   75            53                                                DSCG.sup.2)   16            20                                                ______________________________________                                         DSCG: sodium chromoglycate; 1) subcutaneously; 2) orally; 3) dose: 30         mg/kg of body weight                                                     

Pharmacological Test 3

Toxicity test by single administration

A homogeneous suspension of the compound of Example 46 according to thepresent invention in an aqueous carboxymethyl cellulose was orallyadministered compellingly to female ICR mice of five week old having anaverage body weight of about 20 g. All animals were survived at a doseof 1 g/kg of the compound of Example 46 and showed no particularsymptoms.

What is claimed is:
 1. A tricyclic benzazepine or benzothiazepinecompound represented by the formula (I): ##STR20## wherein --Z--representscarbonyl; a group --CR⁶ R⁷ --, wherein R⁶ and R⁷, which may bethe same or different, representhydrogen, hydroxyl, C₁₋₁₂ alkyloptionally substituted by halogen, hydroxyl or C₃₋₇ cycloalkyl, or C₁₋₁₂alkoxy optionally substituted by halogen, hydroxyl or C₃₋₇ cycloalkyl; agroup --(C═N--OR⁸)--, wherein R⁸ representshydrogen or C₁₋₁₂ alkyloptionally substituted by C₃₋₇ cycloalkyl, or a group --S(O)_(n) --,wherein n is an integer of 0-2; --R representshydrogen; C₁₋₆ alkyloptionally substituted by halogen, hydroxyl, C₃₋₇ cycloalkyl or C₁₋₄alkoxy; phenyl C₁₋₄ alkyl, of which the hydrogen atoms on the benzenering may be optionally substituted by halogen, hydroxyl, nitro, C₁₋₄alkyl or C₁₋₄ alkoxy; or a protective group of the triazole group; --R¹representshydrogen; hydroxyl; C₁₋₂ alkyl optionally substituted byhalogen, hydroxyl or C₃₋₇ cycloalkyl; phenyl C₁₋₄ alkyl, of which thehydrogen atoms on the benzene ring may be optionally substituted byhalogen, hydroxyl, nitro, C₁₋₄ alkyl or C₁₋₄ alkoxy; --R², R³, R⁴ andR⁵, which may be the same or different, represent any one of thefollowing (a)-(v):(a) hydrogen; (b) halogen; (c) hydroxyl which may beprotected; (d) cyano; (e) nitro; (f) thiol; (g) formyl; (h) C₁₋₁₂ alkyloptionally substituted by halogen, hydroxyl or C₃₋₇ cycloalkyl; (i)phenyl optionally substituted by C₁₋₄ alkyl; (j) phenyl C₁₋₄ alkyl, ofwhich the hydrogen atoms on the benzene ring may be optionallysubstituted by halogen, hydroxyl, nitro, amino, sulfonyl, C₁₋₄ alkyl orC₁₋₄ alkoxy; (k) C₂₋₁₂ alkenyl, which includes one or more carbon-carbondouble bonds and may be optionally substituted by(1) halogen, (2) cyano,(3) C₃₋₇ cycloalkyl, (4) phenyl, (5) a group --COR⁹, wherein R⁹representshydrogen, C₁₋₆ alkyl, or phenyl optionally substituted byhalogen, hydroxyl, C₁₋₄ alkyl or C₁₋₄ alkoxy, (6) a group --COOR¹⁰,wherein R¹⁰ represents hydrogen or C₁₋₆ alkyl, (7) a group --CONR¹¹ R¹²,wherein R¹¹ and R¹², which may be the same or different, represent(i)hydrogen, (ii) C₁₋₆ alkyl optionally substituted by hydroxyl; C₁₋₄alkoxy; amino which may be optionally substituted by C₁₋₄ alkyl, C₁₋₁₆alkylcarbonyl, benzoyl, α-naphthoyl, β-naphthoyl or sulfonyl; phenylwhich may be optionally substituted by halogen, hydroxyl, C₁₋₄ alkyl(which may be optionally substituted by a saturated 5-7 memberedheterocyclic ring containing one or two nitrogen atoms, whichheterocyclic ring is selected from the group consisting of piperidino,4-piperidinyl, 1-pyrrolidinyl, piperadinyl and morpholino and which maybe optionally substituted by C₁₋₄ alkyl), C₁₋₄ alkoxy or carboxyl; or asaturated or unsaturated 5-7 membered heterocyclic ring containing oneor more of oxygen atoms, nitrogen atoms or sulfur atoms, whichheterocyclic ring is selected from the group consisting of pyridine,imidazole, oxazole, thiazole, pyrimidine, furan, thiophene, pyrrole,pyrrolidine, piperidine, tetrahydrofuran, oxazoline, quinoline andisoquinoline and which heterocyclic ring may be optionally substitutedby C₁₋₄ alkyl or phenyl C₁₋₄ alkyl or may be a bicyclic ring fused withanother ring, or (iii) phenyl, or (iv) a saturated or unsaturated 5-7membered heterocyclic ring which is formed by R¹¹ and R¹² together withthe nitrogen atom R¹¹ and R¹² attached thereto and may further containone or more of oxygen atoms, nitrogen atoms or sulfur atoms, whichheterocyclic ring is selected from the group consisting of tetrazole,thiazole, imidazole, pyridine, pyrimidine and pyrazine and whichheterocyclic ring may be optionally substituted by C₁₋₄ alkyl or phenylC₁₋₄ alkyl or may be a bicyclic ring fused with another ring; (l) C₁₋₁₂alkoxy optionally substituted by(1) halogen, (2) hydroxyl, (3) cyano,(4) C₃₋₇ cycloalkyl, (5) epoxy, (6) phenyl optionally substituted byhalogen, hydroxyl, nitro, C₁₋₄ alkyl or C₁₋₄ alkoxy, (7) C₁₋₄ alkoxy,(8) phenoxy optionally substituted by halogen, hydroxyl, C₁₋₄ alkyl,C₁₋₄ alkoxy or carboxyl, (9) amino optionally substituted by C₁₋₄ alkyl,C₁₋₆ alkylcarbonyl, benzoyl, α-naphthoyl, β-naphthoyl or sulfonyl, (10)a group --COR¹³, wherein R¹³ representshydrogen, C₁₋₆ alkyl, phenyloptionally substituted by halogen, hydroxyl, C₁₋₄ alkyl or C₁₋₄ alkoxy,or phenyl C₁₋₄ alkyl, of which the hydrogen atoms on the benzene ringmay be optionally substituted by halogen, hydroxyl, C₁₋₄ alkyl, C₁₋₄alkoxy or carboxyl, (11) a group --COOR¹⁴, wherein R¹⁴ representshydrogen or C₁₋₆ alkyl, (12) a group --CONR¹⁵ R¹⁶, wherein R¹⁵ and R¹⁶may be the same or different and representhydrogen, C₁₋₆ alkyloptionally substituted by hydroxyl, C₁₋₄ alkoxy, or amino (which may beoptionally substituted by C₁₋₄ alkyl, C₁₋₆ alkylcarbonyl, benzoyl,α-naphthoyl, β-naphthoyl or sulfonyl), or phenyl, or (13) a saturated orunsaturated 5-7 membered heterocyclic ring containing one or more ofoxygen atoms, nitrogen atoms or sulfur atoms, which heterocyclic ring isselected from the group consisting of piperidino, 4-piperidinyl,1-pyrrolidinyl, piperazinyl and morpholino and which heterocyclic ringmay be optionally substituted by C₁₋₄ alkyl or phenyl C₁₋₄ alkyl, or maybe a bicyclic ring fused with another ring, (m) phenoxy optionallysubstituted by hydroxyl, C₁₋₄ alkyl, C₁₋₄ alkoxy or carboxyl; (n) C₂₋₁₂alkenyloxy optionally substituted by C₁₋₄ alkyl or phenyl; (o) C₁₋₁₂alkylthio optionally substituted by hydroxyl, C₃₋₇ cycloalkyl, C₂₋₄alkenyl, C₁₋₄ alkoxy or benzyl; (p) a group --C═N--OR²⁶, wherein R²⁶representshydrogen, C₁₋₆ alkyl, phenyl C₁₋₄ alkyl, or phenyl; (q) agroup --(CH₂)_(m) OR¹⁷, wherein m is an integer of 1-4, and R¹⁷representshydrogen, C₁₋₆ alkyl optionally substituted by halogen,hydroxyl or C₃₋₇ cycloalkyl, phenyl C₁₋₄ alkyl, of which the hydrogenatoms of the benzene ring may be optionally substituted by hydroxyl,C₁₋₄ alkyl or C₁₋₄ alkoxy, phenyl, or C₁₋₄ alkylcarbonyl; (r) a group--(CH₂)_(k) --COR¹⁸, wherein k is an integer of 1-4, and R¹⁸representshydrogen, C₁₋₁₂ alkyl optionally substituted by hydroxyl, C₃₋₇cycloalkyl or C₁₋₄ alkoxy, or phenyl optionally substituted by halogen,hydroxyl, nitro, C₁₋₄ alkyl or C₁₋₄ alkoxy; (s) a group --(CH₂)_(j)--COOR¹⁹, wherein j is an integer of 0-4, and R¹⁹ representshydrogen,C₁₋₁₂ alkyl optionally substituted by halogen, hydroxyl or C₁₋₄ alkoxy,or benzyl, of which the hydrogen atoms on the benzene ring may beoptionally substituted by C₃₋₇ cycloalkyl, C₂₋₄ alkenyl, halogen,hydroxyl, nitro, C₁₋₄ alkyl or C₁₋₄ alkoxy, or a protective group ofcarboxyl; (t) a group --(CH₂)_(p) --NR²⁰ R²¹, wherein p is an integer of0-4, and R²⁰ and R²¹ may be the same or different and represent(1)hydrogen, (2) C₁₋₆ alkyl optionally substituted by hydroxyl, amino(which may be optionally substituted by C₁₋₄ alkyl, C₁₋₆ alkylcarbonyl,benzoyl, α-naphthoyl, β-naphthoyl or sulfonyl), C₃₋₇ cycloalkyl or C₁₋₄alkoxy, (3) phenyl C₁₋₄ alkyl, of which the hydrogen atoms on thebenzene ring may be optionally substituted by halogen, hydroxyl, nitro,cyano, C₁₋₄ alkyl, C₁₋₄ alkoxy or carboxyl, (4) a group --COR²⁷, whereinR²⁷ representshydrogen, C₁₋₄ alkyl optionally substituted by hydroxyl orcarboxyl, or C₃₋₇ cycloalkyl optionally substituted by hydroxyl orcarboxyl, or (5) a group --SO₂ R²⁸, wherein R²⁸ representsC₁₋₄ alkyl,phenyl optionally substituted by halogen, hydroxyl, nitro, cyano, C₁₋₄alkyl, C₁₋₄ alkoxy or carboxyl, or amino optionally substituted by C₁₋₄alkyl, C₁₋₆ alkylcarbonyl, benzoyl, α-naphthoyl, β-naphthoyl orsulfonyl, or (6) a saturated or unsaturated 5-7 membered heterocyclicring formed by R²⁰ and R²¹ together with the nitrogen atom R²⁰ and R²¹attached thereto, which heterocyclic ring may further contain one ormore of oxygen atoms, nitrogen atoms or sulfur atoms, which heterocyclicring is selected from the group consisting of piperazino, piperidino,morpholino, succinimido, indolyl, isoindolyl, phthalimido andbenzothiazolyl and may be optionally substituted by C₁₋₄ alkyl orcarbonyl; (u) a group --(CH₂)_(q) --CONR²² R²³, whereinq is an integerof 0-4, and R²² and R²³ may be the same or different and representhydrogen, C₁₋₆ alkyl (optionally substituted by C₃₋₇ cycloalkyl), C₃₋₇cycloalkyl, phenyl (optionally substituted by hydroxyl, C₁₋₄ alkyl orC₁₋₄ alkoxy), sulfonyl, or a saturated or unsaturated 5-7 memberedheterocyclic ring formed by R²² and R²³ together with the nitrogen atomR²² and R²³ attached thereto, which heterocyclic ring may furthercontain one or more of oxygen atoms, nitrogen atoms or sulfur atoms,which heterocyclic ring is selected from the group consisting ofpiperazino, piperidino, morpholino, succinimido, indolyl, isoindolyl,phthalimido and benzothiazolyl and may be optionally substituted by C₁₋₄alkyl; (v) a group --NR²⁹ R³⁰, wherein R²⁹ and R³⁰, which may be thesame or different, represent(1) hydrogen, (2) C₁₋₆ alkyl optionallysubstituted byhalogen, hydroxyl, C₁₋₄ alkoxy, or amino which may beoptionally substituted by C₁₋₄ alkyl, C₁₋₆ alkylcarbonyl, benzoyl,α-naphthoyl, β-naphthoyl or sulfonyl, (3) phenyl C₁₋₄ alkyl, of whichthe hydrogen atoms on the benzene ring may be optionally substituted byhalogen, hydroxyl, nitro, cyano, C₁₋₄ alkyl or C₁₋₄ alkoxy, (4) a group--COR³¹, wherein R³¹ representshydrogen, C₁₋₆ alkyl optionallysubstituted by halogen, hydroxyl, C₁₋₄ alkyl or C₁₋₄ alkoxy, or phenyloptionally substituted by halogen, hydroxyl, nitro, cyano, C₁₋₄ alkyl orC₁₋₄ alkoxy, (5) a group --COOR³², wherein R³² representsC₁₋₆ alkyl, orphenyl which may be optionally substituted by halogen, hydroxyl, nitro,cyano, C₁₋₄ alkyl or C₁₋₄ alkoxy, (6) a group --CONR³⁴ R³⁵, wherein R³⁴and R³⁵ may be the same or different and representhydrogen, C₁₋₆ alkyloptionally substituted by C₁₋₄ alkyl or amino which may be optionallysubstituted by C₁₋₄ alkyl, C₁₋₆ alkylcarbonyl, benzoyl, α-naphthoyl,β-naphthoyl or sulfonyl, or phenyl, or (7) a group SO₂ R³⁶, wherein R³⁶representsC₁₋₆ alkyl, phenyl optionally substituted by C₁₋₄ alkyl, C₁₋₄alkoxy or halogen, or α- or β-naphthyl,or a pharmacologically acceptablesalt thereof.
 2. A compound according to claim 1, wherein Z representscarbonyl, R represents hydrogen, and R¹, R², R³, R⁴ and R⁵ representhydrogen or (h) C₁₋₁₂ alkyl.
 3. A compound according to claim 1, whereinZ represents carbonyl, R and R¹ represent hydrogen, and R², R³, R⁴ andR⁵ represent hydrogen or (l) C₁₋₁₂ alkoxy.
 4. A compound according toclaim 1, wherein Z represents carbonyl, R, R¹, R² and R⁵ representhydrogen, and R³ and R⁴ represent hydrogen or (h) C₁₋₁₂ alkyl.
 5. Acompound according to claim 1, wherein Z represents carbonyl, R, R¹, R²and R⁵ represent hydrogen, and R³ and R⁴ represent hydrogen or (k) C₂₋₁₂alkenyl.
 6. A compound according to claim 1, wherein Z representscarbonyl, R, R¹, R² and R⁵ represent hydrogen, and R³ and R⁴ representhydrogen or (l) C₁₋₁₂ alkoxy.
 7. A compound according to claim 1,wherein Z represents carbonyl, R, R¹, R², R⁴ and R⁵ represent hydrogen,and R³ represent (h) C₁₋₁₂ alkyl.
 8. A compound according to claim 1,wherein Z represents carbonyl, R, R¹, R², R⁴ and R⁵ represent hydrogen,and R³ represents (k) C₂₋₁₂ alkenyl.
 9. A compound according to claim 1,wherein Z represents carbonyl, R, R¹, R², R⁴ and R⁵ represent hydrogen,and R³ represents (l) C₁₋₁₂ alkoxy.
 10. A compound according to claim 1,wherein Z represents carbonyl, R, R¹, R², R⁴ and R⁵ represent hydrogen,and R⁴ represents (k) C₂₋₁₂ alkenyl.
 11. A compound according to claim1, wherein Z represents carbonyl, R, R¹, R², R³ and R⁵ representhydrogen, and R⁴ represents (l) C₁₋₁₂ alkoxy.
 12. A compound accordingto claim 1, wherein Z represents carbonyl, R, R¹, R² and R⁵ representhydrogen, and R³ and R⁴ represent (r) a group --(CH₂)_(k) --COR¹⁸, (t) agroup --(CH₂)_(p) --NR²⁰ R²¹, (u) a group --(CH₂)_(q) --CONR²² R²³ or(v) a group --NR²⁹ R³⁰.
 13. A compound according to claim 1, wherein Zrepresents a group --CR⁶ R⁷ --, R and R¹ represent hydrogen, and R², R³,R⁴ and R⁵ represent hydrogen, (h) C₁₋₁₂ alkyl, (k) C₂₋₁₂ alkenyl, or (l)C₁₋₁₂ alkoxy.
 14. A compound according to claim 13, wherein one of R⁶and R⁷ represents hydrogen, and the other represents (h) C₁₋₁₂ alkyl, or(l) C₁₋₁₂ alkoxy.
 15. A compound according to claim 1, wherein Zrepresents a group --(C═N--OR⁸)--, --R⁸ represents hydrogen or C₁₋₁₂alkyl, R and R¹ represent hydrogen, and R², R³, R⁴ and R⁵ representhydrogen, (h) C₁₋₁₂ alkyl, (k) C₂₋₁₂ alkenyl, or (l) C₁₋₁₂ alkoxy.
 16. Acompound according to claim 1, wherein Z represents a group S(O)_(n), Rand R¹ represent hydrogen, and R², R³, R⁴ and R⁵ represent hydrogen, (h)C₁₋₁₂ alkyl, or (l) C₁₋₁₂ alkoxy.
 17. A compound selected from the groupconsisting of7-methyl-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine 7-ethyl-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine, 7-methoxy-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine, 7-ethoxy-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine, 8-methyl-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine, 8-methoxy-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine, 8-ethoxy-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine, 7-cyanomethoxy-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine, 7-methoxycarbonylmethoxy-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine,8-methoxycarbonylmethoxy-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine,7-(4-methoxybenzoylmethoxy)-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine, 7-acetonyloxy-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine,7-(2-methoxycarbonyl-(E)-ethenyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine,7-(2-methoxycarbonylethyl)-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine,7-(2-carboxy-(E)-ethenyl)-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine, 7-(2-cyano-(E)-ethenyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine,7-(3-oxo-(E)-butenyl)-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine 7,8-dimethyl-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine, 7,8-dimethoxy-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine, 7-methyl-8-methoxy-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine,7-(2-methoxycarbonyl-2-methyl-(E)-ethenyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine,7-(2-(4-methoxybenzoyl)-(E)-ethenyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine,7-(2-(N-benzylcarbamoyl)-(E)-ethenyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine,4(5H),10-dioxo-7-(2-(N-(2-pyridyl)methylcarbamoyl)-(E)-ethenyl)-1H-1,2,3-triazolo4,5-c! 1!benzazepine,7-(N-(4-(4-methyl-1-piperazinyl)methylbenzylcarbamoyl)-(E)-ethenyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine,4(5H),10-dioxo-7-(2-(N-(1H-tetrazol-5-yl)carbamoyl)-(E)-ethenyl)-1H-1,2,3-triazolo4,5-c! 1!benzazepine,7-(hydroxyimino)methyl-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine, 7-(methoxyimino)methyl-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine,7-(benzyloxyimino)methyl-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine,7-(N-acetyl-N-propylaminomethyl)-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine,7-(N-(3-carboxypropanoyl)-N-propylaminomethyl-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine,7-(N-benzylaminomethyl)-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine,7-(2-(N,N-dimethylamino)ethylaminomethyl-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine,7-(N-(4-carboxybutyryl)aminomethyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine,7-(N-acetylaminomethyl)-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine,7-(N-methanesulfonylaminomethyl)-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine,7-(N-benzenesulfonylaminomethyl)-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine, 4(5H),10-dioxo-7-(3-phenoxypropoxy)-1H-1,2,3-triazolo4,5-c! 1!benzazepine,4(5H),10-dioxo-7-(3-phenylpropoxy)-1H-1,2,3-triazolo 4,5-c!1!benzazepine, 4(5H),10-dioxo-7-(2-oxo-4-phenylbutoxy)-1H-1,2,3-triazolo4,5-c! 1!benzazepine,7-(2-hydroxy-4-phenylbutoxy)-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine,7-(3-(4-benzyl-1-piperazinyl)propoxy)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine,4(5H),10-dioxo-7-(3-(1-piperidinyl)propoxy)-1H-1,2,3-triazolo 4,5-c!1!benzazepine,7-(3-(N,N-dimethylamino)propoxy)-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine, 8-(2-methoxyethoxy)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine,8-(2-methoxyphenacyloxy)-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine, 7-formyl-5-hydroxy-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine, 4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine, 6-methyl-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine 7-methyl-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine, 8-methyl-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine, 9-methyl-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine, 10(9H)-oxo-3H-1,2,3-triazolo 4,5-b! 1,5!benzothiazepine,10(9H)-oxo-3H-1,2,3-triazolo 4,5-b! 1,5!benzothiazepine 4-oxide,10(9H)-oxo-3H-1,2,3-triazolo 4,5-b! 1,5!benzothiazepine 4,4-dioxide,7-(N-(4-fluorobenzenesulfonyl)aminomethyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine,7-(N-(4-chlorobenzenesulfonyl)aminomethyl)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine,7-(2-methoxyphenacyloxy)-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine, 7-(4-chlorophenacyloxy)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine,4(5H),10-dioxo-7-(2-phenoxyethoxy)-1H-1,2,3-triazolo 4,5-c!1!benzazepine, 8-(4-methoxyphenacyloxy)-4(5H),10-dioxo-1H-1,2,3-triazolo4,5-c! 1!benzazepine,7-(4-methylbenzoyl)amino-4(5H),10-dioxo-1H-1,2,3-triazolo 4,5-c!1!benzazepine, andpharmacologically acceptable salts thereof.
 18. Apharmaceutical composition for the treatment or prophylaxis of allergicdiseases, comprising as an effective ingredient a compound according toany one of claims 2-17 or 23 or a pharmacologically acceptable saltthereof, and a pharmacologically acceptable carrier.